|
Inhibition of PARP1 by flashplate scintillation proximity assay
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
Year : 2008
Volume : 51
Issue : 20
First Page : 6581
Last Page : 6591
Authors : Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM.
Abstract : Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
|
Inhibition of recombinant PARP2 by flashplate scintillation proximity assay
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
Year : 2008
Volume : 51
Issue : 20
First Page : 6581
Last Page : 6591
Authors : Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM.
Abstract : Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
|
Ex vivo inhibition of PARP1 in human SW620 cells assessed as amount of poly(ADP-ribose) by whole cell assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
Year : 2008
Volume : 51
Issue : 20
First Page : 6581
Last Page : 6591
Authors : Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM.
Abstract : Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
|
Inhibition of PARP1/PARP2 in human SKOV3 cells assessed as reduction in H2O2-induced PARylation incubated for 4 hrs prior to H2O2 treatment
|
Homo sapiens
|
20.9
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of a series of benzo[de][1,7]naphthyridin-7(8H)-ones bearing a functionalized longer chain appendage as novel PARP1 inhibitors.
Year : 2013
Volume : 56
Issue : 7
First Page : 2885
Last Page : 2903
Authors : Ye N, Chen CH, Chen T, Song Z, He JX, Huan XJ, Song SS, Liu Q, Chen Y, Ding J, Xu Y, Miao ZH, Zhang A.
Abstract : A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.
|
Inhibition of human recombinant PARP1 after 1 hr by ELISA
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of a series of benzo[de][1,7]naphthyridin-7(8H)-ones bearing a functionalized longer chain appendage as novel PARP1 inhibitors.
Year : 2013
Volume : 56
Issue : 7
First Page : 2885
Last Page : 2903
Authors : Ye N, Chen CH, Chen T, Song Z, He JX, Huan XJ, Song SS, Liu Q, Chen Y, Ding J, Xu Y, Miao ZH, Zhang A.
Abstract : A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.
|
SANGER: Inhibition of human NCI-H209 cell growth in a cell viability assay.
|
Homo sapiens
|
915.56
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human COLO-800 cell growth in a cell viability assay.
|
Homo sapiens
|
441.64
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EoL-1-cell cell growth in a cell viability assay.
|
Homo sapiens
|
564.46
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Inhibition of PARP7 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Fragment-based ligand design of novel potent inhibitors of tankyrases.
Year : 2013
Volume : 56
Issue : 11
First Page : 4497
Last Page : 4508
Authors : Larsson EA, Jansson A, Ng FM, Then SW, Panicker R, Liu B, Sangthongpitag K, Pendharkar V, Tai SJ, Hill J, Dan C, Ho SY, Cheong WW, Poulsen A, Blanchard S, Lin GR, Alam J, Keller TH, Nordlund P.
Abstract : Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
|
Inhibition of PARP11 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Fragment-based ligand design of novel potent inhibitors of tankyrases.
Year : 2013
Volume : 56
Issue : 11
First Page : 4497
Last Page : 4508
Authors : Larsson EA, Jansson A, Ng FM, Then SW, Panicker R, Liu B, Sangthongpitag K, Pendharkar V, Tai SJ, Hill J, Dan C, Ho SY, Cheong WW, Poulsen A, Blanchard S, Lin GR, Alam J, Keller TH, Nordlund P.
Abstract : Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
|
Inhibition of PARP6 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Fragment-based ligand design of novel potent inhibitors of tankyrases.
Year : 2013
Volume : 56
Issue : 11
First Page : 4497
Last Page : 4508
Authors : Larsson EA, Jansson A, Ng FM, Then SW, Panicker R, Liu B, Sangthongpitag K, Pendharkar V, Tai SJ, Hill J, Dan C, Ho SY, Cheong WW, Poulsen A, Blanchard S, Lin GR, Alam J, Keller TH, Nordlund P.
Abstract : Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
|
Inhibition of PARP2 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : J. Med. Chem.
Title : Fragment-based ligand design of novel potent inhibitors of tankyrases.
Year : 2013
Volume : 56
Issue : 11
First Page : 4497
Last Page : 4508
Authors : Larsson EA, Jansson A, Ng FM, Then SW, Panicker R, Liu B, Sangthongpitag K, Pendharkar V, Tai SJ, Hill J, Dan C, Ho SY, Cheong WW, Poulsen A, Blanchard S, Lin GR, Alam J, Keller TH, Nordlund P.
Abstract : Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
|
Inhibition of PARP3 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : J. Med. Chem.
Title : Fragment-based ligand design of novel potent inhibitors of tankyrases.
Year : 2013
Volume : 56
Issue : 11
First Page : 4497
Last Page : 4508
Authors : Larsson EA, Jansson A, Ng FM, Then SW, Panicker R, Liu B, Sangthongpitag K, Pendharkar V, Tai SJ, Hill J, Dan C, Ho SY, Cheong WW, Poulsen A, Blanchard S, Lin GR, Alam J, Keller TH, Nordlund P.
Abstract : Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
|
Inhibition of PARP1 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
97.0
%
|
|
Journal : J. Med. Chem.
Title : Fragment-based ligand design of novel potent inhibitors of tankyrases.
Year : 2013
Volume : 56
Issue : 11
First Page : 4497
Last Page : 4508
Authors : Larsson EA, Jansson A, Ng FM, Then SW, Panicker R, Liu B, Sangthongpitag K, Pendharkar V, Tai SJ, Hill J, Dan C, Ho SY, Cheong WW, Poulsen A, Blanchard S, Lin GR, Alam J, Keller TH, Nordlund P.
Abstract : Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
|
Inhibition of PARP1 in human Jurkat cells assessed as reduction of cell viability after 96 hrs by MTS assay in presence of 100 uM of temozolomide
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.
Year : 2013
Volume : 23
Issue : 16
First Page : 4501
Last Page : 4505
Authors : Gangloff AR, Brown J, de Jong R, Dougan DR, Grimshaw CE, Hixon M, Jennings A, Kamran R, Kiryanov A, O'Connell S, Taylor E, Vu P.
Abstract : Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
|
Inhibition of human PARP1 catalytic activity after 10 mins by ELISA
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.
Year : 2013
Volume : 23
Issue : 16
First Page : 4501
Last Page : 4505
Authors : Gangloff AR, Brown J, de Jong R, Dougan DR, Grimshaw CE, Hixon M, Jennings A, Kamran R, Kiryanov A, O'Connell S, Taylor E, Vu P.
Abstract : Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
|
Inhibition of recombinant human GST-fused PARP-1 expressed in Escherichia coli after 30 mins by fluorescence assay
|
Homo sapiens
|
4.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors.
Year : 2014
Volume : 22
Issue : 3
First Page : 1089
Last Page : 1103
Authors : Cincinelli R, Musso L, Merlini L, Giannini G, Vesci L, Milazzo FM, Carenini N, Perego P, Penco S, Artali R, Zunino F, Pisano C, Dallavalle S.
Abstract : 7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals.
|
Inhibition of GST-tagged recombinant human PARP-1 expressed in Escherichia coli after 30 mins by fluorescence-based assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold.
Year : 2014
Volume : 24
Issue : 2
First Page : 462
Last Page : 466
Authors : Giannini G, Battistuzzi G, Vesci L, Milazzo FM, De Paolis F, Barbarino M, Guglielmi MB, Carollo V, Gallo G, Artali R, Dallavalle S.
Abstract : Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA integrity and programmed cell death. A virtual screening of commercial libraries led to the identification of five novel scaffolds with inhibitory profile in the low nanomolar range. A hit-to-lead optimization led to the identification of a group of new potent PARP-1 inhibitors, acyl-piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-propionic acid. Molecular modeling studies highlighted the preponderant role of the propanoyl side chain.
|
Inhibition of PARP-1 in human HeLa cells assessed as decrease of H2O2-induced PARylation after 3 hrs by fluorescence assay
|
Homo sapiens
|
2.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors.
Year : 2014
Volume : 22
Issue : 3
First Page : 1089
Last Page : 1103
Authors : Cincinelli R, Musso L, Merlini L, Giannini G, Vesci L, Milazzo FM, Carenini N, Perego P, Penco S, Artali R, Zunino F, Pisano C, Dallavalle S.
Abstract : 7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals.
|
Inhibition of PARP-1 (unknown origin) assessed as incorporation of biotinylated poly ADP-ribose onto histone proteins by colorimetric analysis in presence of GSH and GSTP1
|
Homo sapiens
|
15.5
nM
|
|
Journal : J. Med. Chem.
Title : Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.
Year : 2014
Volume : 57
Issue : 6
First Page : 2292
Last Page : 2302
Authors : Maciag AE, Holland RJ, Kim Y, Kumari V, Luthers CE, Sehareen WS, Biswas D, Morris NL, Ji X, Anderson LM, Saavedra JE, Keefer LK.
Abstract : We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N-N(O)═NO- group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.
|
Inhibition of recombinant human PARP-8 at 10 uM relative to control
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.
Year : 2014
Volume : 57
Issue : 6
First Page : 2807
Last Page : 2812
Authors : Liscio P, Carotti A, Asciutti S, Karlberg T, Bellocchi D, Llacuna L, Macchiarulo A, Aaronson SA, Schüler H, Pellicciari R, Camaioni E.
Abstract : Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.
|
Inhibition of recombinant human PARP-10 at 10 uM relative to control
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.
Year : 2014
Volume : 57
Issue : 6
First Page : 2807
Last Page : 2812
Authors : Liscio P, Carotti A, Asciutti S, Karlberg T, Bellocchi D, Llacuna L, Macchiarulo A, Aaronson SA, Schüler H, Pellicciari R, Camaioni E.
Abstract : Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.
|
Inhibition of recombinant human PARP-12 at 10 uM relative to control
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.
Year : 2014
Volume : 57
Issue : 6
First Page : 2807
Last Page : 2812
Authors : Liscio P, Carotti A, Asciutti S, Karlberg T, Bellocchi D, Llacuna L, Macchiarulo A, Aaronson SA, Schüler H, Pellicciari R, Camaioni E.
Abstract : Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.
|
Inhibition of PARP-1 (unknown origin) using biotinylated NAD+ as substrate after 60 mins by spectrophotometry
|
Homo sapiens
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and structure-activity relationship of novel 2,3-dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 inhibitors.
Year : 2014
Volume : 57
Issue : 13
First Page : 5579
Last Page : 5601
Authors : Patel MR, Bhatt A, Steffen JD, Chergui A, Murai J, Pommier Y, Pascal JM, Trombetta LD, Fronczek FR, Talele TT.
Abstract : Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
|
Inhibition of human recombinant PARP-1 after 1 hr by ELISA
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.
Year : 2014
Volume : 24
Issue : 12
First Page : 2669
Last Page : 2673
Authors : Chen J, Peng H, He J, Huan X, Miao Z, Yang C.
Abstract : The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC50s against PARP-1 enzyme.
|
In vivo inhibition of PARP activity in peripheral blood mononuclear cells of advanced breast cancer patient with BRCA1/2 mutations at 400 mg dosed twice daily
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Development of synthetic lethality anticancer therapeutics.
Year : 2014
Volume : 57
Issue : 19
First Page : 7859
Last Page : 7873
Authors : Fang B.
Abstract : The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy.
|
In vivo inhibition of PARP activity in tumor tissue of advanced breast cancer patient with BRCA1/2 mutations at 400 mg dosed twice daily
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Development of synthetic lethality anticancer therapeutics.
Year : 2014
Volume : 57
Issue : 19
First Page : 7859
Last Page : 7873
Authors : Fang B.
Abstract : The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy.
|
Inhibition of human PARP1
|
Homo sapiens
|
84.96
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors.
Year : 2014
Volume : 24
Issue : 16
First Page : 3739
Last Page : 3743
Authors : Wang LX, Zhou XB, Xiao ML, Jiang N, Liu F, Zhou WX, Wang XK, Zheng ZB, Li S.
Abstract : We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
|
Inhibition of human PARP1 at 1 umol
|
Homo sapiens
|
89.97
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors.
Year : 2014
Volume : 24
Issue : 16
First Page : 3739
Last Page : 3743
Authors : Wang LX, Zhou XB, Xiao ML, Jiang N, Liu F, Zhou WX, Wang XK, Zheng ZB, Li S.
Abstract : We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination.
Year : 2015
Volume : 58
Issue : 8
First Page : 3302
Last Page : 3314
Authors : Jones P, Wilcoxen K, Rowley M, Toniatti C.
Abstract : Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.
|
Binding affinity to recombinant human HisGST-tagged PARP-1 catalytic domain by surface plasmon resonance analysis
|
Homo sapiens
|
0.24
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.
Year : 2015
Volume : 58
Issue : 17
First Page : 6875
Last Page : 6898
Authors : Papeo G, Posteri H, Borghi D, Busel AA, Caprera F, Casale E, Ciomei M, Cirla A, Corti E, D'Anello M, Fasolini M, Forte B, Galvani A, Isacchi A, Khvat A, Krasavin MY, Lupi R, Orsini P, Perego R, Pesenti E, Pezzetta D, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Sola F, Zuccotto F, Felder ER, Donati D, Montagnoli A.
Abstract : The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
|
Binding affinity to recombinant human HisGST-tagged PARP-2 catalytic domain by surface plasmon resonance analysis
|
Homo sapiens
|
0.28
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.
Year : 2015
Volume : 58
Issue : 17
First Page : 6875
Last Page : 6898
Authors : Papeo G, Posteri H, Borghi D, Busel AA, Caprera F, Casale E, Ciomei M, Cirla A, Corti E, D'Anello M, Fasolini M, Forte B, Galvani A, Isacchi A, Khvat A, Krasavin MY, Lupi R, Orsini P, Perego R, Pesenti E, Pezzetta D, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Sola F, Zuccotto F, Felder ER, Donati D, Montagnoli A.
Abstract : The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
|
Inhibition of PARP1 (unknown origin) incubated for 10 mins using biotinylated NAD+ and activated DNA by colorimetric assay
|
Homo sapiens
|
11.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo.
Year : 2015
Volume : 58
Issue : 21
First Page : 8683
Last Page : 8693
Authors : Zmuda F, Malviya G, Blair A, Boyd M, Chalmers AJ, Sutherland A, Pimlott SL.
Abstract : Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An (123)I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [(123)I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [(123)I]5 as a noninvasive PARP-1 SPECT imaging agent.
|
Inhibition of PARP1 in human G7 cells incubated for 60 mins by immunofluorescence assay
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo.
Year : 2015
Volume : 58
Issue : 21
First Page : 8683
Last Page : 8693
Authors : Zmuda F, Malviya G, Blair A, Boyd M, Chalmers AJ, Sutherland A, Pimlott SL.
Abstract : Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An (123)I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [(123)I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [(123)I]5 as a noninvasive PARP-1 SPECT imaging agent.
|
Inhibition of PARP1 in human T98G cells incubated for 60 mins by immunofluorescence assay
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo.
Year : 2015
Volume : 58
Issue : 21
First Page : 8683
Last Page : 8693
Authors : Zmuda F, Malviya G, Blair A, Boyd M, Chalmers AJ, Sutherland A, Pimlott SL.
Abstract : Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An (123)I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [(123)I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [(123)I]5 as a noninvasive PARP-1 SPECT imaging agent.
|
Inhibition of full length human PARP1 expressed in Baculovirus infected Sf9 insect cells using activated DNA as substrate after 1 hr by streptavidin-horseradish peroxidase-based luminescence assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering.
Year : 2015
Volume : 25
Issue : 24
First Page : 5743
Last Page : 5747
Authors : Johannes JW, Almeida L, Daly K, Ferguson AD, Grosskurth SE, Guan H, Howard T, Ioannidis S, Kazmirski S, Lamb ML, Larsen NA, Lyne PD, Mikule K, Ogoe C, Peng B, Petteruti P, Read JA, Su N, Sylvester M, Throner S, Wang W, Wang X, Wu J, Ye Q, Yu Y, Zheng X, Scott DA.
Abstract : The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
|
Inhibition of human PARP2 (2 to 583 residues) expressed in Baculovirus infected Sf9 insect cells using activated DNA as substrate after 1 hr by streptavidin-horseradish peroxidase-based luminescence assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering.
Year : 2015
Volume : 25
Issue : 24
First Page : 5743
Last Page : 5747
Authors : Johannes JW, Almeida L, Daly K, Ferguson AD, Grosskurth SE, Guan H, Howard T, Ioannidis S, Kazmirski S, Lamb ML, Larsen NA, Lyne PD, Mikule K, Ogoe C, Peng B, Petteruti P, Read JA, Su N, Sylvester M, Throner S, Wang W, Wang X, Wu J, Ye Q, Yu Y, Zheng X, Scott DA.
Abstract : The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
|
Inhibition of PARP3 (unknown origin) using activated DNA as substrate after 1 hr by streptavidin-horseradish peroxidase-based luminescence assay
|
Homo sapiens
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering.
Year : 2015
Volume : 25
Issue : 24
First Page : 5743
Last Page : 5747
Authors : Johannes JW, Almeida L, Daly K, Ferguson AD, Grosskurth SE, Guan H, Howard T, Ioannidis S, Kazmirski S, Lamb ML, Larsen NA, Lyne PD, Mikule K, Ogoe C, Peng B, Petteruti P, Read JA, Su N, Sylvester M, Throner S, Wang W, Wang X, Wu J, Ye Q, Yu Y, Zheng X, Scott DA.
Abstract : The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
|
Inhibition of human PARP1 using [3H]NAD as substrate after 1 min by microplate scintillation counting analysis
|
Homo sapiens
|
1.94
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent.
Year : 2016
Volume : 59
Issue : 1
First Page : 335
Last Page : 357
Authors : Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE.
Abstract : We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.
|
Inhibition of PARP in human LoVo cells assessed as inhibition of poly(ADP)-ribose polymerization for 30 mins by fluorescence assay
|
Homo sapiens
|
3.57
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent.
Year : 2016
Volume : 59
Issue : 1
First Page : 335
Last Page : 357
Authors : Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE.
Abstract : We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.
|
Cytotoxicity against BRCA2-deficient human Capan1 cells
|
Homo sapiens
|
259.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent.
Year : 2016
Volume : 59
Issue : 1
First Page : 335
Last Page : 357
Authors : Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE.
Abstract : We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.
|
Cytotoxicity against BRCA1-deficient human MX1 cells
|
Homo sapiens
|
23.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent.
Year : 2016
Volume : 59
Issue : 1
First Page : 335
Last Page : 357
Authors : Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE.
Abstract : We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.
|
In Vitro Screening Assay: PARP-1 can catalyze the NAD-dependent addition of poly (ADP-ribose) to adjacent nuclear proteins such as histone. The activity of PARP was determined by detecting biotin coupled ADP-ribose that attaches to histone using chemiluminescence method with HT Universal Chemiluminescent PARP Assay Kit With Histone-coated Strip Wells purchased from TREVIGEN. The positive control compound was AZD-2281 purchased from SelleckChem.Method: The kit is based on ELISA. X ul sample/well, Y ul PARP enzyme/well and PARP cocktail 25 ul/well with a total volume of 50 ul/well were added into a 96-well plate coated with histone. Meanwhile, blank control (without enzyme and sample) and negative control (without sample) were set. The plate was incubated at room temperature for 60 min; washed with 1xPBS (+0.1% TritonX-100) for twice; Strep-HRP 50 ul/well was added and incubated at room temperature for 60 min; and then washed with 1xPBS (+0.1% TritonX-100) for twice.
|
None
|
12.0
nM
|
|
Title : Poly (ADP-ribose) polymerase inhibitor
Year : 2015
|
ELISA Assay: The HTb-PARP1 positive clones were obtained using the full-length PARP1 plasmid, through PCR amplification, enzyme digestion, ligation, and transformation into DH5a. The plasmids were extracted and determined by enzyme cleavage, and then transformed into DH10Bac. Bacmid/PARP is determined by PCR and sequencing. TNI was transfected, the viruses were collected, and cells were lysed. PARP1 protein was purified by affinity chromatography and determined by Western blotting. A plate was coated by substrate histone, NAD+ and DNA, as well as expressed PARP1 enzyme, was placed into 96-well plate reaction system. Various reaction conditions were optimized and ultimately determined.
|
None
|
50.0
nM
|
|
ELISA Assay: The HTb-PARP1 positive clones were obtained using the full-length PARP1 plasmid, through PCR amplification, enzyme digestion, ligation, and transformation into DH5a. The plasmids were extracted and determined by enzyme cleavage, and then transformed into DH10Bac. Bacmid/PARP is determined by PCR and sequencing. TNI was transfected, the viruses were collected, and cells were lysed. PARP1 protein was purified by affinity chromatography and determined by Western blotting. A plate was coated by substrate histone, NAD+ and DNA, as well as expressed PARP1 enzyme, was placed into 96-well plate reaction system. Various reaction conditions were optimized and ultimately determined.
|
None
|
43.0
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Cellular Assay: Based on the preliminary PARP1 inhibition evaluation of compounds at molecular level by ELISA, compounds were further evaluated for their cellular inhibition against PARP1 using a proliferation inhibition model.
|
None
|
86.32
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Enzyme Assay: In order to test the selectivity of substituents on piperazinotriazole ring within the PARP family, the selectivity of compound S3 and positive compound AZD2281 were tested.
|
None
|
0.9
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Enzyme Assay: In order to test the selectivity of substituents on piperazinotriazole ring within the PARP family, the selectivity of compound S3 and positive compound AZD2281 were tested.
|
None
|
0.45
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Enzyme Assay: In order to test the selectivity of substituents on piperazinotriazole ring within the PARP family, the selectivity of compound S3 and positive compound AZD2281 were tested.
|
Homo sapiens
|
320.0
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Enzyme Assay: In order to test the selectivity of substituents on piperazinotriazole ring within the PARP family, the selectivity of compound S3 and positive compound AZD2281 were tested.
|
None
|
10.4
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Enzyme Assay: In order to test the selectivity of substituents on piperazinotriazole ring within the PARP family, the selectivity of compound S3 and positive compound AZD2281 were tested.
|
None
|
5.2
nM
|
|
Title : Substituted [1,2,4]triazolo[4,3-a]pyrazines as PARP-1 inhibitors
Year : 2016
|
Inhibition of full length recombinant human His6-tagged PARP1 expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
1.38
nM
|
|
Inhibition of full length recombinant human His6-tagged PARP1 expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of recombinant human His6-tagged PARP1 C-3-zinc finger domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
69.18
nM
|
|
Inhibition of recombinant human His6-tagged PARP1 C-3-zinc finger domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
18.9
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of recombinant human His6-tagged PARP1 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
10.23
nM
|
|
Inhibition of recombinant human His6-tagged PARP1 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of full length recombinant human His6-tagged PARP2 expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
12.3
nM
|
|
Inhibition of full length recombinant human His6-tagged PARP2 expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
12.3
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of recombinant human His6-tagged PARP2 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
251.19
nM
|
|
Inhibition of recombinant human His6-tagged PARP2 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
251.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of full length recombinant human His6-tagged PARP3 expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
229.09
nM
|
|
Inhibition of full length recombinant human His6-tagged PARP3 expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
230.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of recombinant human His6-tagged PARP4 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
410.0
nM
|
|
Inhibition of recombinant human His6-tagged PARP4 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
407.38
nM
|
|
Journal : J Med Chem
Title : Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1262
Last Page : 1271
Authors : Thorsell AG, Ekblad T, Karlberg T, Löw M, Pinto AF, Trésaugues L, Moche M, Cohen MS, Schüler H.
Abstract : Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
|
Inhibition of recombinant human PARP1 expressed in Escherichia coli BL21(DE3) using histone as substrate measured after 1 hr in presence of biotinylated NAD+ by ELISA
|
Homo sapiens
|
2.09
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of 2-substituted 1H-benzo[d]immidazole-4-carboxamide derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors with in vivo anti-tumor activity.
Year : 2017
Volume : 132
First Page : 26
Last Page : 41
Authors : Zhou J, Ji M, Zhu Z, Cao R, Chen X, Xu B.
Abstract : Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent PARP-1 inhibitors also had similar inhibitory activities against PARP-2. Among all the synthesized compounds, compound 10a and 11e displayed strong potentiation effects on temozolomide (TMZ) in MX-1 cells (PF50 = 7.10, PF50 = 4.17). In vivo tumor growth inhibition was investigated using compound 10a in combination with TMZ, and it was demonstrated that compound 10a could strongly potentiate the cytotoxicity of TMZ in MX-1 xenograft tumor model. Two co-crystal structures of compounds 11b and 15e complexed with PARP-1 were achieved and demonstrated a unique binding mode of these benzo-imidazole derivatives.
|
Inhibition of recombinant full length human N-terminal GST-tagged PARP1 expressed in baculovirus infected Sf9 cells using biotinylated substrate after 1 hr by UV/Vis spectrophotometric analysis
|
Homo sapiens
|
3.59
nM
|
|
Journal : Bioorg Med Chem
Title : Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy.
Year : 2017
Volume : 25
Issue : 15
First Page : 4100
Last Page : 4109
Authors : Yuan Z, Chen S, Sun Q, Wang N, Li D, Miao S, Gao C, Chen Y, Tan C, Jiang Y.
Abstract : Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.
|
Inhibition of recombinant human N-terminal GST-tagged PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 cells using biotinylated substrate after 1 hr by UV/Vis spectrophotometric analysis
|
Homo sapiens
|
2.81
nM
|
|
Journal : Bioorg Med Chem
Title : Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy.
Year : 2017
Volume : 25
Issue : 15
First Page : 4100
Last Page : 4109
Authors : Yuan Z, Chen S, Sun Q, Wang N, Li D, Miao S, Gao C, Chen Y, Tan C, Jiang Y.
Abstract : Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.
|
Inhibition of recombinant human PARP-1 expressed in Escherichia coli BL21 (DE3) using sheared DNA as substrate in presence of biotinylated NAD after 1 hr by ELISA
|
Homo sapiens
|
8.1
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors.
Year : 2017
Volume : 25
Issue : 15
First Page : 4045
Last Page : 4054
Authors : Zhao H, Ji M, Cui G, Zhou J, Lai F, Chen X, Xu B.
Abstract : The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.
|
Inhibition of recombinant human PARP-2 expressed in Escherichia coli BL21 (DE3) using sheared DNA as substrate in presence of biotinylated NAD after 1 hr by ELISA
|
Homo sapiens
|
1.7
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors.
Year : 2017
Volume : 25
Issue : 15
First Page : 4045
Last Page : 4054
Authors : Zhao H, Ji M, Cui G, Zhou J, Lai F, Chen X, Xu B.
Abstract : The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.
|
Inhibition of PARP1 (unknown origin) by ELISA
|
Homo sapiens
|
19.1
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy.
Year : 2017
Volume : 138
First Page : 514
Last Page : 531
Authors : Chen W, Guo N, Qi M, Dai H, Hong M, Guan L, Huan X, Song S, He J, Wang Y, Xi Y, Yang X, Shen Y, Su Y, Sun Y, Gao Y, Chen Y, Ding J, Tang Y, Ren G, Miao Z, Li J.
Abstract : Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.
|
Antiproliferative activity against human MDA-MB-436 cells after 7 days by CCK8 or SRB assay
|
Homo sapiens
|
39.3
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy.
Year : 2017
Volume : 138
First Page : 514
Last Page : 531
Authors : Chen W, Guo N, Qi M, Dai H, Hong M, Guan L, Huan X, Song S, He J, Wang Y, Xi Y, Yang X, Shen Y, Su Y, Sun Y, Gao Y, Chen Y, Ding J, Tang Y, Ren G, Miao Z, Li J.
Abstract : Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.
|
Cytotoxicity against BRCA2 deficient Chinese hamster VC8 cells after 3 days by CCK8 or SRB assay
|
Cricetulus griseus
|
565.6
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy.
Year : 2017
Volume : 138
First Page : 514
Last Page : 531
Authors : Chen W, Guo N, Qi M, Dai H, Hong M, Guan L, Huan X, Song S, He J, Wang Y, Xi Y, Yang X, Shen Y, Su Y, Sun Y, Gao Y, Chen Y, Ding J, Tang Y, Ren G, Miao Z, Li J.
Abstract : Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.
|
Antiproliferative activity against human Capan1 cells after 7 days by CCK8 or SRB assay
|
Homo sapiens
|
399.3
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy.
Year : 2017
Volume : 138
First Page : 514
Last Page : 531
Authors : Chen W, Guo N, Qi M, Dai H, Hong M, Guan L, Huan X, Song S, He J, Wang Y, Xi Y, Yang X, Shen Y, Su Y, Sun Y, Gao Y, Chen Y, Ding J, Tang Y, Ren G, Miao Z, Li J.
Abstract : Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.
|
Inhibition of PARP1 (unknown origin) assessed as reduction in biotinylated poly(ADP-ribose) incorporation on to histone protein by ELISA based colorimetric assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy.
Year : 2017
Volume : 138
First Page : 1135
Last Page : 1146
Authors : Yuan Z, Chen S, Chen C, Chen J, Chen C, Dai Q, Gao C, Jiang Y.
Abstract : PARP-1 could repair the DNA damages induced by Topo inhibitors, therefore inhibiting Topo and PARP-1 simultaneously might be able to overcome resistance and improve outcomes. In this study a series of 4-amidobenzimidazole acridines were designed and synthesized as dual Topo and PARP-1 inhibitors. Compound 11l displayed good inhibitory activities against Topo and PARP-1, as well as significantly inhibited cancer cells proliferation. Further mechanistic evaluations indicated that 11l treatment in MCF-7 cells induced accumulated DNA double-strand breaks, prompted remarkable apoptosis, and caused prominent G0/G1 cell cycle arrest. Moreover, 11l greatly suppressed tumor growth in mice, and displayed favorable metabolic properties in liver microsomes. Our study suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for cancer therapy and 11l represented a potential lead compound for development of antitumor agents.
|
Binding affinity to PARP1 in human OVCAR8 cells assessed as reduction in [125I]-KX1 binding by gamma counting analysis
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity.
Year : 2018
Volume : 61
Issue : 12
First Page : 5367
Last Page : 5379
Authors : Reilly SW, Puentes LN, Wilson K, Hsieh CJ, Weng CC, Makvandi M, Mach RH.
Abstract : Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 ± 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 ± 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.
|
Cytotoxicity against human BRCA1-deficient UWB1.289 cells assessed as reduction in cell viability after 4 to 7 days by cell-titer glo assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J Med Chem
Title : Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity.
Year : 2018
Volume : 61
Issue : 12
First Page : 5367
Last Page : 5379
Authors : Reilly SW, Puentes LN, Wilson K, Hsieh CJ, Weng CC, Makvandi M, Mach RH.
Abstract : Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 ± 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 ± 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.
|
Inhibition of recombinant human PARP1 using histone as substrate after 1 hr in presence of NAD+ by ELISA
|
Homo sapiens
|
11.0
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.
Year : 2018
Volume : 145
First Page : 389
Last Page : 403
Authors : Chen X, Huan X, Liu Q, Wang Y, He Q, Tan C, Chen Y, Ding J, Xu Y, Miao Z, Yang C.
Abstract : The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.
|
Inhibition of recombinant human PARP2 using histone as substrate after 1.5 hr in presence of NAD+ by ELISA
|
Homo sapiens
|
3.0
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.
Year : 2018
Volume : 145
First Page : 389
Last Page : 403
Authors : Chen X, Huan X, Liu Q, Wang Y, He Q, Tan C, Chen Y, Ding J, Xu Y, Miao Z, Yang C.
Abstract : The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.
|
Inhibition of human full-length N-terminal GST-tagged PARP1 expressed in baculovirus infected Sf9 insect cells using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay
|
Homo sapiens
|
1.2
nM
|
|
Inhibition of human full-length N-terminal GST-tagged PARP1 expressed in baculovirus infected Sf9 insect cells using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay
|
Homo sapiens
|
1.175
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of human N-terminal GST-tagged PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 insect cells using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay
|
Homo sapiens
|
0.5
nM
|
|
Inhibition of human N-terminal GST-tagged PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 insect cells using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay
|
Homo sapiens
|
0.3981
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of human full-length N-terminal GST-tagged PARP3 expressed in baculovirus infected Sf9 insect cells at 500 nM using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of human N-terminal GST-tagged TNKS1 (1001 to 1327 residues) expressed in baculovirus infected Sf9 insect cells at 500 nM using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay relative to control
|
Homo sapiens
|
64.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of human N-terminal GST-tagged TNKS2 (667 to 1166 residues) expressed in baculovirus infected Sf9 insect cells at 500 nM using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay relative to control
|
Homo sapiens
|
61.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of PARP8 (unknown origin) at 500 nM using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay relative to control
|
Homo sapiens
|
68.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of human N-terminal FLAG-tagged/C-terminal Strep-tagged PARP10 (805 to 1025 residues) expressed in baculovirus infected Sf9 insect cells at 500 nM using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay relative to control
|
Homo sapiens
|
51.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Inhibition of human N-terminal His/GST-tagged PARP14 (1470 to 1801 residues) expressed in baculovirus infected Sf9 insect cells at 500 nM using histone as substrate measured after 1 hr by horseradish peroxidase-coupled chemiluminescence assay relative to control
|
Homo sapiens
|
7.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Cytotoxicity against BRCA1-deficient human SUM149 cells measured after 6 days by microscopic analysis
|
Homo sapiens
|
400.0
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Year : 2019
Volume : 62
Issue : 11
First Page : 5330
Last Page : 5357
Authors : Velagapudi UK, Langelier MF, Delgado-Martin C, Diolaiti ME, Bakker S, Ashworth A, Patel BA, Shao X, Pascal JM, Talele TT.
Abstract : Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC<sub>50</sub> = 434 nM) led to a tetrazolyl analogue (51, IC<sub>50</sub> = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC<sub>50</sub> = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC<sub>50</sub> values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC<sub>50</sub> values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC<sub>50</sub> = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
|
Binding affinity to full length His-tagged PARP1 (unknown origin) after 11 mins in presence of NAD+ by TR-FRET assay
|
Homo sapiens
|
0.787
nM
|
|
Journal : MedChemComm
Title : Controlling cellular distribution of drugs with permeability modifying moieties.
Year : 2019
Volume : 10
Issue : 6
First Page : 974
Last Page : 984
Authors : Richardson PL, Marin VL, Koeniger SL, Baranczak A, Wilsbacher JL, Kovar PJ, Bacon-Trusk PE, Cheng M, Hopkins TA, Haman ST, Vasudevan A.
Abstract : Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties <i>via</i> short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H<sub>3</sub>, 5HT<sub>1A</sub>, β<sub>2</sub>AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
|
Antiproliferative activity against BRCA deficient human DLD1 cells by Celltiter-Glo assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : MedChemComm
Title : Controlling cellular distribution of drugs with permeability modifying moieties.
Year : 2019
Volume : 10
Issue : 6
First Page : 974
Last Page : 984
Authors : Richardson PL, Marin VL, Koeniger SL, Baranczak A, Wilsbacher JL, Kovar PJ, Bacon-Trusk PE, Cheng M, Hopkins TA, Haman ST, Vasudevan A.
Abstract : Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties <i>via</i> short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H<sub>3</sub>, 5HT<sub>1A</sub>, β<sub>2</sub>AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
|
Inhibition of N-terminal GST-tagged human PARP1 expressed in a Baculovirus infected Sf9 insect cells using biotinylated substrate incubated for 1 hr by colorimetric method
|
Homo sapiens
|
139.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Year : 2019
Volume : 27
Issue : 18
First Page : 3979
Last Page : 3997
Authors : Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB.
Abstract : Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.
|
Inhibition of PARP2 (unknown origin)
|
Homo sapiens
|
2.81
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Year : 2019
Volume : 27
Issue : 18
First Page : 3979
Last Page : 3997
Authors : Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB.
Abstract : Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.
|
Inhibition of PARP1 (unknown origin) by colorimetric assay
|
Homo sapiens
|
3.59
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Year : 2019
Volume : 27
Issue : 18
First Page : 3979
Last Page : 3997
Authors : Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB.
Abstract : Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.
|
Inhibition of human PARP1 expressed in Escherichia coli incubated for 10 mins by colorimetric assay
|
Homo sapiens
|
8.39
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Year : 2019
Volume : 27
Issue : 18
First Page : 3979
Last Page : 3997
Authors : Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB.
Abstract : Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.
|
Inhibition of recombinant human full length N-terminal GST- tagged PARP1 expressed in baculovirus infected sf9 cells using Colorimetric HRP as substrate incubated for 30 mins by UV/Vis spectrophotometer analysis
|
Homo sapiens
|
1.8
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation.
Year : 2019
Volume : 182
First Page : 111621
Last Page : 111621
Authors : Boraei ATA, Singh PK, Sechi M, Satta S.
Abstract : PARP-1, a nuclear protein, is one of the key member of the DNA repair assembly and thereby emerged as an attractive target in anti-cancer drug discovery. PARP-1 plays a key role in terms of base excision repair, which is an important pathway for cell survival in breast cancer with BRCA1/BRCA2-mutation. In this scenario, the goal of this study was to identify novel prototypes of PARP-1 inhibitors for the development of antitumor therapeutics to treat breast cancer. Thus, a structure-based drug design exploration was first conducted using an in-house library, focusing on triazole-thione and alkylsulfanyl-triazole scaffold. Hits with good binding affinity and better predicted inhibitory potential were also tested for their PARP-1 inhibitory activity. Moreover, the selected compounds were evaluated for their cytotoxicity in-vitro. This approach led to the identification of few novel compounds showing interesting anti-proliferative potential in low micromolar range. Results disclosed that the identified lead molecules were efficiently impeding cell migration and cell proliferation, potentially by interfering with PARP-1 enzymatic activities.
|
Inhibition of recombinant human PARP1 using histone as substrate after 1 hr in presence of biotinylated NAD+ by ELISA
|
Homo sapiens
|
5.012
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Antiproliferative activity against human A2780 cells measured after 7 days by Celltiter-glo assay
|
Homo sapiens
|
741.31
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Inhibition of recombinant human PARP2 using histone as substrate after 1 hr in presence of biotinylated NAD+ by ELISA
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.
Year : 2020
Volume : 63
Issue : 1
First Page : 122
Last Page : 139
Authors : Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y.
Abstract : Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound <b>15</b> stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC<sub>50</sub> values greater than 8. Compound <b>15</b> displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, <b>15</b> showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that <b>15</b>, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
|
Inhibition of recombinant human full length C-terminal His-tagged PARP1 expressed in Sf9 insect cells preincubated for 15 mins followed by NAD+ addition and measured after 40 mins by fluorescence based assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of naphthacemycins as a novel class of PARP1 inhibitors.
Year : 2019
Volume : 29
Issue : 15
First Page : 1904
Last Page : 1908
Authors : Shen W, Lu X, Zhu J, Mu Y, Xu Y, Gao J, Zhang X, Zheng Z.
Abstract : Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein that plays important roles in a variety of nuclear processes, and it has been proved a prominent target in oncology for its key function in DNA damage repair. In this study, we discovered a series of naphthacemycins as a new class of PARP1 inhibitors from a microbial metabolites library via high-throughput screening. Compound I, one of this series of compounds, could reduce cellular poly (ADP-ribose) level, trap PARP1 on the damaged DNA and elevate the level of γ-H2AX, and showed the selective cytotoxicity against BRCA1-deficient cell line. Our study provided a potential scaffold for the development of new PARP1 inhibitors in cancer therapy.
|
Antiproliferative activity against human MDA-MB-436 cells harboring BRCA1 mutation incubated for 2 to 5 days by MTT assay
|
Homo sapiens
|
220.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of naphthacemycins as a novel class of PARP1 inhibitors.
Year : 2019
Volume : 29
Issue : 15
First Page : 1904
Last Page : 1908
Authors : Shen W, Lu X, Zhu J, Mu Y, Xu Y, Gao J, Zhang X, Zheng Z.
Abstract : Poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein that plays important roles in a variety of nuclear processes, and it has been proved a prominent target in oncology for its key function in DNA damage repair. In this study, we discovered a series of naphthacemycins as a new class of PARP1 inhibitors from a microbial metabolites library via high-throughput screening. Compound I, one of this series of compounds, could reduce cellular poly (ADP-ribose) level, trap PARP1 on the damaged DNA and elevate the level of γ-H2AX, and showed the selective cytotoxicity against BRCA1-deficient cell line. Our study provided a potential scaffold for the development of new PARP1 inhibitors in cancer therapy.
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel 5-fluoro-1H-benzimidazole-4-carboxamide derivatives as potent PARP-1 inhibitors.
Year : 2016
Volume : 26
Issue : 16
First Page : 4127
Last Page : 4132
Authors : Wang J, Wang X, Li H, Ji D, Li Y, Xu Y, Zhu Q.
Abstract : A series of novel 5-fluorine-benzimidazole-4-carboxamide analogs were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibitory activity. Compounds possessed high intrinsic PARP-1 inhibitory potency have been evaluated in vitro cellular assays to measure the potentiation effect of cytotoxic agents against cancer cell line. These efforts led to the identification of compound 10f, which displayed strong inhibition against the PARP-1 enzyme with an IC50 of 43.7nM, excellent cell inhibitory activity in HCT116 cells (IC50=7.4μM) and potentiation of temozolomide cytotoxicity in cancer cell line A549 (PF50=1.6).
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
20.44
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.78
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
4.19
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors.
Year : 2020
Volume : 30
Issue : 8
First Page : 127036
Last Page : 127036
Authors : Tian Y, Xie Z, Liao C.
Abstract : Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamide, a series of novel 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid derivatives were designed and synthesized. All efforts led to a good dual PARP-1/HDAC-1 inhibitor, compound 4, with IC<sub>50</sub> values of 4.2 and 340 nM against PARP-1 and HDAC-1, which were as potent as olaparib and chidamide respectively. The MTT assay further demonstrated that compound 4 had potent inhibitory activities against BRCA1/2-proficient K562 and MDA-MB-231 cells with GI<sub>50</sub> values of 5.6 and 4.3 μM, respectively. Therefore, our results suggested that compound 4 could be a promising dual PARP-1/HDAC-1 inhibitor for further studies. In addition, a few excellent PARP-1 inhibitors such as 7-9 and HDAC-1 inhibitors such as 12 were serendipitously discovered, which also could be further studied in our next work.
|
Inhibition of N-terminal GST-tagged human full length PARP1 (2 to 1041 residues) expressed in baculovirus infected Sf9 cells using histone mixture (H2A and H2B) and biotinylated NAD+ as substrate in presence of activated DNA incubated for 60 mins by chemiluminescence assay
|
Homo sapiens
|
0.9
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.
Year : 2020
Volume : 28
Issue : 24
First Page : 115819
Last Page : 115819
Authors : Karche NP,Bhonde M,Sinha N,Jana G,Kukreja G,Kurhade SP,Jagdale AR,Tilekar AR,Hajare AK,Jadhav GR,Gupta NR,Limaye R,Khedkar N,Thube BR,Shaikh JS,Rao Irlapati N,Phukan S,Gole G,Bommakanti A,Khanwalkar H,Pawar Y,Kale R,Kumar R,Gupta R,Praveen Kumar VR,Wahid S,Francis A,Bhat T,Kamble N,Patil V,Nigade PB,Modi D,Pawar S,Naidu S,Volam H,Pagdala V,Mallurwar S,Goyal H,Bora P,Ahirrao P,Singh M,Kamalakannan P,Naik KR,Kumar P,Powar RG,Shankar RB,Bernstein PR,Gundu J,Nemmani K,Narasimham L,George KS,Sharma S,Bakhle D,Kamboj RK,Palle VP
Abstract : The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
|
Inhibition of N-terminal GST-tagged human PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 cells using histone mixture (H2A and H2B) and biotinylated NAD+ as substrate in presence of activated DNA incubated for 60 mins by chemiluminescence assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.
Year : 2020
Volume : 28
Issue : 24
First Page : 115819
Last Page : 115819
Authors : Karche NP,Bhonde M,Sinha N,Jana G,Kukreja G,Kurhade SP,Jagdale AR,Tilekar AR,Hajare AK,Jadhav GR,Gupta NR,Limaye R,Khedkar N,Thube BR,Shaikh JS,Rao Irlapati N,Phukan S,Gole G,Bommakanti A,Khanwalkar H,Pawar Y,Kale R,Kumar R,Gupta R,Praveen Kumar VR,Wahid S,Francis A,Bhat T,Kamble N,Patil V,Nigade PB,Modi D,Pawar S,Naidu S,Volam H,Pagdala V,Mallurwar S,Goyal H,Bora P,Ahirrao P,Singh M,Kamalakannan P,Naik KR,Kumar P,Powar RG,Shankar RB,Bernstein PR,Gundu J,Nemmani K,Narasimham L,George KS,Sharma S,Bakhle D,Kamboj RK,Palle VP
Abstract : The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
|
Anticancer activity against human MDA-MB-436 cells harboring BRCA mutant xenografted in SCID/nude mouse assessed as tumor growth regression at 50 mg/kg, po bid and measured up to 5 weeks post-drug administration
|
Homo sapiens
|
40.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.
Year : 2020
Volume : 28
Issue : 24
First Page : 115819
Last Page : 115819
Authors : Karche NP,Bhonde M,Sinha N,Jana G,Kukreja G,Kurhade SP,Jagdale AR,Tilekar AR,Hajare AK,Jadhav GR,Gupta NR,Limaye R,Khedkar N,Thube BR,Shaikh JS,Rao Irlapati N,Phukan S,Gole G,Bommakanti A,Khanwalkar H,Pawar Y,Kale R,Kumar R,Gupta R,Praveen Kumar VR,Wahid S,Francis A,Bhat T,Kamble N,Patil V,Nigade PB,Modi D,Pawar S,Naidu S,Volam H,Pagdala V,Mallurwar S,Goyal H,Bora P,Ahirrao P,Singh M,Kamalakannan P,Naik KR,Kumar P,Powar RG,Shankar RB,Bernstein PR,Gundu J,Nemmani K,Narasimham L,George KS,Sharma S,Bakhle D,Kamboj RK,Palle VP
Abstract : The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
|
Potentiation of anticancer activity against human MDA-MB-436 cells harboring BRCA mutant xenografted in SCID/nude mouse assessed as tumor growth inhibition at 3 mg/kg, po bid for 12 days co-administered with TMZ measured up to 9 weeks post-drug administration
|
Homo sapiens
|
39.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.
Year : 2020
Volume : 28
Issue : 24
First Page : 115819
Last Page : 115819
Authors : Karche NP,Bhonde M,Sinha N,Jana G,Kukreja G,Kurhade SP,Jagdale AR,Tilekar AR,Hajare AK,Jadhav GR,Gupta NR,Limaye R,Khedkar N,Thube BR,Shaikh JS,Rao Irlapati N,Phukan S,Gole G,Bommakanti A,Khanwalkar H,Pawar Y,Kale R,Kumar R,Gupta R,Praveen Kumar VR,Wahid S,Francis A,Bhat T,Kamble N,Patil V,Nigade PB,Modi D,Pawar S,Naidu S,Volam H,Pagdala V,Mallurwar S,Goyal H,Bora P,Ahirrao P,Singh M,Kamalakannan P,Naik KR,Kumar P,Powar RG,Shankar RB,Bernstein PR,Gundu J,Nemmani K,Narasimham L,George KS,Sharma S,Bakhle D,Kamboj RK,Palle VP
Abstract : The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
|
Potentiation of anticancer activity against human CAPAN-1 cells harboring BRCA mutant xenografted in SCID/nude mouse assessed as tumor growth inhibition at 3 mg/kg, po bid for 12 days co-administered with TMZ measured up to 9 weeks post-drug administration
|
Homo sapiens
|
49.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.
Year : 2020
Volume : 28
Issue : 24
First Page : 115819
Last Page : 115819
Authors : Karche NP,Bhonde M,Sinha N,Jana G,Kukreja G,Kurhade SP,Jagdale AR,Tilekar AR,Hajare AK,Jadhav GR,Gupta NR,Limaye R,Khedkar N,Thube BR,Shaikh JS,Rao Irlapati N,Phukan S,Gole G,Bommakanti A,Khanwalkar H,Pawar Y,Kale R,Kumar R,Gupta R,Praveen Kumar VR,Wahid S,Francis A,Bhat T,Kamble N,Patil V,Nigade PB,Modi D,Pawar S,Naidu S,Volam H,Pagdala V,Mallurwar S,Goyal H,Bora P,Ahirrao P,Singh M,Kamalakannan P,Naik KR,Kumar P,Powar RG,Shankar RB,Bernstein PR,Gundu J,Nemmani K,Narasimham L,George KS,Sharma S,Bakhle D,Kamboj RK,Palle VP
Abstract : The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
|
Potentiation of anticancer activity against human SK-ES-1 cells harboring EWSF1 translocation xenografted in SCID/nude mouse assessed as tumor growth inhibition at 3 mg/kg, po bid for 12 days co-administered with TMZ measured up to 9 weeks post drug administration
|
Homo sapiens
|
39.45
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.
Year : 2020
Volume : 28
Issue : 24
First Page : 115819
Last Page : 115819
Authors : Karche NP,Bhonde M,Sinha N,Jana G,Kukreja G,Kurhade SP,Jagdale AR,Tilekar AR,Hajare AK,Jadhav GR,Gupta NR,Limaye R,Khedkar N,Thube BR,Shaikh JS,Rao Irlapati N,Phukan S,Gole G,Bommakanti A,Khanwalkar H,Pawar Y,Kale R,Kumar R,Gupta R,Praveen Kumar VR,Wahid S,Francis A,Bhat T,Kamble N,Patil V,Nigade PB,Modi D,Pawar S,Naidu S,Volam H,Pagdala V,Mallurwar S,Goyal H,Bora P,Ahirrao P,Singh M,Kamalakannan P,Naik KR,Kumar P,Powar RG,Shankar RB,Bernstein PR,Gundu J,Nemmani K,Narasimham L,George KS,Sharma S,Bakhle D,Kamboj RK,Palle VP
Abstract : The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
|
Inhibition of PARP-1 (unknown origin)
|
Homo sapiens
|
5.22
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors.
Year : 2021
Volume : 31
First Page : 127710
Last Page : 127710
Authors : Xiang HY,Chen JY,Huan XJ,Chen Y,Gao ZB,Ding J,Miao ZH,Yang CH
Abstract : A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CCs of 340 and 106 nM respectively. The PK property of 15b was also investigated here.
|
Inhibition of PARP-2 (unknown origin)
|
Homo sapiens
|
1.87
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors.
Year : 2021
Volume : 31
First Page : 127710
Last Page : 127710
Authors : Xiang HY,Chen JY,Huan XJ,Chen Y,Gao ZB,Ding J,Miao ZH,Yang CH
Abstract : A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CCs of 340 and 106 nM respectively. The PK property of 15b was also investigated here.
|
Inhibition of human PARP-1 catalytic domain (662 to 1011 residues) expressed in Escherichia coli BL21(DE3) cells incubated for 0.5 hrs by fluorescence polarization assay based DNA trapping activity assay
|
Homo sapiens
|
16.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
Year : 2020
Volume : 63
Issue : 24
First Page : 15541
Last Page : 15563
Authors : Wang H,Ren B,Liu Y,Jiang B,Guo Y,Wei M,Luo L,Kuang X,Qiu M,Lv L,Xu H,Qi R,Yan H,Xu D,Wang Z,Huo CX,Zhu Y,Zhao Y,Wu Y,Qin Z,Su D,Tang T,Wang F,Sun X,Feng Y,Peng H,Wang X,Gao Y,Liu Y,Gong W,Yu F,Liu X,Wang L,Zhou C
Abstract : Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
|
Inhibition of PARP-1 in human HeLa cells incubated for 18 hrs in presence of H2O2
|
Homo sapiens
|
0.4
nM
|
|
Journal : J Med Chem
Title : Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
Year : 2020
Volume : 63
Issue : 24
First Page : 15541
Last Page : 15563
Authors : Wang H,Ren B,Liu Y,Jiang B,Guo Y,Wei M,Luo L,Kuang X,Qiu M,Lv L,Xu H,Qi R,Yan H,Xu D,Wang Z,Huo CX,Zhu Y,Zhao Y,Wu Y,Qin Z,Su D,Tang T,Wang F,Sun X,Feng Y,Peng H,Wang X,Gao Y,Liu Y,Gong W,Yu F,Liu X,Wang L,Zhou C
Abstract : Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
|
Inhibition of PARP-2 (unknown origin) pre-incubated for 30 mins before addition of activated DNA and NAD by chemiluminescent assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : J Med Chem
Title : Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
Year : 2020
Volume : 63
Issue : 24
First Page : 15541
Last Page : 15563
Authors : Wang H,Ren B,Liu Y,Jiang B,Guo Y,Wei M,Luo L,Kuang X,Qiu M,Lv L,Xu H,Qi R,Yan H,Xu D,Wang Z,Huo CX,Zhu Y,Zhao Y,Wu Y,Qin Z,Su D,Tang T,Wang F,Sun X,Feng Y,Peng H,Wang X,Gao Y,Liu Y,Gong W,Yu F,Liu X,Wang L,Zhou C
Abstract : Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
|
Inhibition of human PARP-1 catalytic domain (662 to 1011 residues) expressed in Escherichia coli BL21(DE3) cells pre-incubated for 30 mins before addition of activated DNA and NAD by fluorescence based assay
|
Homo sapiens
|
4.8
nM
|
|
Journal : J Med Chem
Title : Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
Year : 2020
Volume : 63
Issue : 24
First Page : 15541
Last Page : 15563
Authors : Wang H,Ren B,Liu Y,Jiang B,Guo Y,Wei M,Luo L,Kuang X,Qiu M,Lv L,Xu H,Qi R,Yan H,Xu D,Wang Z,Huo CX,Zhu Y,Zhao Y,Wu Y,Qin Z,Su D,Tang T,Wang F,Sun X,Feng Y,Peng H,Wang X,Gao Y,Liu Y,Gong W,Yu F,Liu X,Wang L,Zhou C
Abstract : Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
|
Antiproliferative activity against human MDA-MB-436 cells assessed as cell growth inhibition incubated for 7 days by CCK-8 assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : J Med Chem
Title : Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers.
Year : 2020
Volume : 63
Issue : 19
First Page : 11012
Last Page : 11033
Authors : Cao C,Yang J,Chen Y,Zhou P,Wang Y,Du W,Zhao L,Chen Y
Abstract : The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.
|
Antiproliferative activity against human CAPAN-1 cells assessed as cell growth inhibition incubated for 13 days by by CCK-8 assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : J Med Chem
Title : Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers.
Year : 2020
Volume : 63
Issue : 19
First Page : 11012
Last Page : 11033
Authors : Cao C,Yang J,Chen Y,Zhou P,Wang Y,Du W,Zhao L,Chen Y
Abstract : The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.
|
Inhibition of recombinant human C-terminal His-tagged PARP1 expressed in Sf9 insect cells preincubated for 20 mins in presence of activated DNA followed by 32P-NAD+ addition and further incubated for 2 hrs by chemiluminescence assay
|
Homo sapiens
|
3.35
nM
|
|
Journal : J Med Chem
Title : Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers.
Year : 2020
Volume : 63
Issue : 19
First Page : 11012
Last Page : 11033
Authors : Cao C,Yang J,Chen Y,Zhou P,Wang Y,Du W,Zhao L,Chen Y
Abstract : The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.
|
Inhibition of PARP1 (unknown origin) at 10 nM relative to control
|
Homo sapiens
|
91.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel PARP/PI3K dual inhibitors with high efficiency against BRCA-proficient triple negative breast cancer.
Year : 2021
Volume : 213
First Page : 113054
Last Page : 113054
Authors : Wang J,He G,Li H,Ge Y,Wang S,Xu Y,Zhu Q
Abstract : Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468 cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50 mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Title : An elisa-like assay for quantifying enzymatic activities of mono-adp-ribosyltransferases
|
Inhibition of human recombinant GST-tagged PARP-1 expressed in Escherichia coli at 100 nM incubated for 30 mins in presence and NAD by resazurin dye based fluorescence analysis relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Bromophenol-Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer.
Year : 2019
Volume : 62
Issue : 6.0
First Page : 3051
Last Page : 3067
Authors : Guo C,Wang L,Li X,Wang S,Yu X,Xu K,Zhao Y,Luo J,Li X,Jiang B,Shi D
Abstract : Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol-thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC = 29.5 nM) over PARP-2 (IC > 1000 nM) and potent anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 cancer cell lines (IC = 2.39, 5.45, and 4.60 μM), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple anticancer mechanisms, including the induction of apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of HO-triggered PARylation, antiproliferative effects via the production of cytotoxic reactive oxygen species, and autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new anticancer drugs.
|
Antitumor activity against human SKOV3 cells xenografted in Balb/c nude mouse assessed as tumor growth inhibition at 25 mg/kg, po for 21 days and measured every third day
|
Homo sapiens
|
55.73
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Bromophenol-Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer.
Year : 2019
Volume : 62
Issue : 6.0
First Page : 3051
Last Page : 3067
Authors : Guo C,Wang L,Li X,Wang S,Yu X,Xu K,Zhao Y,Luo J,Li X,Jiang B,Shi D
Abstract : Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol-thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC = 29.5 nM) over PARP-2 (IC > 1000 nM) and potent anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 cancer cell lines (IC = 2.39, 5.45, and 4.60 μM), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple anticancer mechanisms, including the induction of apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of HO-triggered PARylation, antiproliferative effects via the production of cytotoxic reactive oxygen species, and autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new anticancer drugs.
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Inhibition of PARP1 (unknown origin) using biotin-NAD+ as substrate incubated for 1 hr by ELISA
|
Homo sapiens
|
1.26
nM
|
|
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
1.1
nM
|
|
|
Inhibition of recombinant human full-length PARP-1 using biotinylated substrate
|
Homo sapiens
|
5.1
nM
|
|
|
Inhibition of recombinant human full-length PARP-2 using biotinylated substrate
|
Homo sapiens
|
1.2
nM
|
|
|
Binding affinity to recombinant human PARP-1 by SPR analysis
|
Homo sapiens
|
0.31
nM
|
|
|
Binding affinity to recombinant human PARP-2 by SPR analysis
|
Homo sapiens
|
0.27
nM
|
|
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Antiproliferative activity against human MDA-MB-231 cells at 1 uM for 10 days by SRB staining based clone formation assay relative to control
|
Homo sapiens
|
12.44
%
|
|
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Antiproliferative activity against human MDA-MB-231 cells at 3 uM for 10 days by SRB staining based clone formation assay relative to control
|
Homo sapiens
|
97.95
%
|
|
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Inhibition of recombinant human PARP1 using NAD+ as substrate incubated for 1 hr by ELISA
|
Homo sapiens
|
2.09
nM
|
|
|
Inhibition of recombinant human PARP2 using NAD+ as substrate incubated for 1 hr by ELISA
|
Homo sapiens
|
2.26
nM
|
|
|
Inhibition of PARP1 (unknown origin) incubated for 45 mins in presence of biotinylated-NAD+ by microplate reader analysis
|
Homo sapiens
|
0.6
nM
|
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