|
Inhibition of human PARP2 by trichloroacetic acid precipitation assay
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Year : 2009
Volume : 52
Issue : 22
First Page : 7170
Last Page : 7185
Authors : Jones P, Altamura S, Boueres J, Ferrigno F, Fonsi M, Giomini C, Lamartina S, Monteagudo E, Ontoria JM, Orsale MV, Palumbi MC, Pesci S, Roscilli G, Scarpelli R, Schultz-Fademrecht C, Toniatti C, Rowley M.
Abstract : We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
|
Inhibition of human PARP1 by SPA
|
Homo sapiens
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Year : 2009
Volume : 52
Issue : 22
First Page : 7170
Last Page : 7185
Authors : Jones P, Altamura S, Boueres J, Ferrigno F, Fonsi M, Giomini C, Lamartina S, Monteagudo E, Ontoria JM, Orsale MV, Palumbi MC, Pesci S, Roscilli G, Scarpelli R, Schultz-Fademrecht C, Toniatti C, Rowley M.
Abstract : We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
|
Inhibition of PARP in hydrogen peroxide-induced human HeLa cells assessed as inhibition DNA-damage-induced PARylation
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Year : 2009
Volume : 52
Issue : 22
First Page : 7170
Last Page : 7185
Authors : Jones P, Altamura S, Boueres J, Ferrigno F, Fonsi M, Giomini C, Lamartina S, Monteagudo E, Ontoria JM, Orsale MV, Palumbi MC, Pesci S, Roscilli G, Scarpelli R, Schultz-Fademrecht C, Toniatti C, Rowley M.
Abstract : We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
|
Inhibition of human TANK1 C-terminal domain by trichloroacetic acid precipitation assay
|
Homo sapiens
|
570.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Year : 2009
Volume : 52
Issue : 22
First Page : 7170
Last Page : 7185
Authors : Jones P, Altamura S, Boueres J, Ferrigno F, Fonsi M, Giomini C, Lamartina S, Monteagudo E, Ontoria JM, Orsale MV, Palumbi MC, Pesci S, Roscilli G, Scarpelli R, Schultz-Fademrecht C, Toniatti C, Rowley M.
Abstract : We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
|
Inhibition of human v-PARP catalytic domain by trichloroacetic acid precipitation assay
|
Homo sapiens
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Year : 2009
Volume : 52
Issue : 22
First Page : 7170
Last Page : 7185
Authors : Jones P, Altamura S, Boueres J, Ferrigno F, Fonsi M, Giomini C, Lamartina S, Monteagudo E, Ontoria JM, Orsale MV, Palumbi MC, Pesci S, Roscilli G, Scarpelli R, Schultz-Fademrecht C, Toniatti C, Rowley M.
Abstract : We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
|
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
|
200.0
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
|
35.0
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
|
32.3
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
|
30.0
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.
|
In vivo inhibition of PARP activity in in BRCA mutation carrying cancer patient with sporadic cancer at >80 mg/day
|
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.
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
2.0
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.
|
Inhibition of PARP in human HeLa cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay
|
Homo sapiens
|
4.0
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.
|
Inhibition of PARP in human A2780 cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay
|
Homo sapiens
|
4.0
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.
|
Inhibition of PARP in BRCA2-deficient human CAPAN-1 cells assessed as inhibition of hydrogen peroxide-induced PARylation by cell-based assay
|
Homo sapiens
|
3.5
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.
|
Toxicity against immunocompromised mouse xenografted with human MDA-MB-436 cells harboring BRCA1 mutant assessed as reduction in body weight at 80 mg/kg, po qd for 1 to 4 weeks
|
Mus musculus
|
10.0
%
|
|
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.
|
Toxicity against immunocompromised mouse xenografted with BRCA2-deficient human CAPAN-1 cells assessed as reduction in body weight at 80 mg/kg, po qd for 2 to 4 weeks
|
Mus musculus
|
10.0
%
|
|
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.
|
Inhibition of PARP activity in tumor of immunocompromised mouse xenografted with human MDA-MB-436 cells harboring BRCA1 mutant assessed as incorporation of [3H]NAD in PAR chains in response to nicked DNA at 50 to 100 mg/kg, po measured after 24 hrs
|
Homo sapiens
|
90.0
%
|
|
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.
|
Inhibition of PARP activity in tumor of immunocompromised mouse xenografted with BRCA2-deficient human Capan1 cells assessed as incorporation of [3H]NAD in PAR chains in response to nicked DNA at 50 to 100 mg/kg, po measured after 24 hrs
|
Homo sapiens
|
90.0
%
|
|
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.
|
Inhibition of PARP-mediated incorporation of [3H]NAD in PAR chains in response to nicked DNA in human PBMC after 24 hrs
|
Homo sapiens
|
50.0
%
|
|
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.
|
Inhibition of human PARP1 using [3H]NAD as substrate after 1 min by microplate scintillation counting analysis
|
Homo sapiens
|
8.05
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
|
650.0
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.
|
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
|
16.22
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
|
16.7
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
|
131.83
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
|
132.0
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
|
15.49
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
|
15.3
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 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
|
295.12
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
|
296.0
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
|
446.0
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
|
446.68
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 PARP12 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
79.0
nM
|
|
Inhibition of recombinant human His6-tagged PARP12 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay
|
Homo sapiens
|
794.33
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.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
2.32
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Cytotoxicity in human MCF7 cells assessed as reduction in cell viability
|
Homo sapiens
|
800.0
nM
|
|
Title : DNA2 inhibitors for cancer treatment
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
3.8
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).
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
3.8
nM
|
|
Inhibition of PARP1 (unknown origin)
|
Homo sapiens
|
3.2
nM
|
|
Journal : Eur J Med Chem
Title : Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update.
Year : 2019
Volume : 165
First Page : 198
Last Page : 215
Authors : Jain PG, Patel BD.
Abstract : Poly (ADP-ribose) Polymerase1 (PARP1) is a member of 17 membered PARP family having diversified biological functions such as synthetic lethality, DNA repair, apoptosis, necrosis, histone binding etc. It is primarily a chromatin-bound nuclear enzyme that gets activated by DNA damage. It binds to DNA signal- and double-strand breaks, does parylation of target proteins (using NAD+ as a substrate) like histones and other DNA repair proteins and modifies them as a part of DNA repair mechanism. Inhibition of PARP1 prevents the DNA repair and leads to cell death. Clinically, PARP1 Inhibitors have shown their potential in treating BRCAm breast and ovarian cancers and trials are going on for the treatment of other solid tumors like pancreatic, prostate, colorectal etc. as a single agent or in combination. There are currently three FDA approved PARP1 inhibitors namely Olaparib, Rucaparib and Niraparib in the market while Veliparib and Talazoparib are in the late stage of clinical development. All these molecules are nonselective PARP1 inhibitors with concurrent inhibition of PARP2 with similar potency. In addition, resistance to marketed PARP1 inhibitors has been reported. Overall, looking at the success rate of PARP1 inhibitors into various solid tumors, there is an urge of a novel and selective PARP1 inhibitors. This review provides an update on various newer heterocyclic PARP1 inhibitors reported in last three years along with their structural design strategies. We classified them into two main chemical classes; NAD analogues and non-NAD analogues and discussed the medicinal chemistry approaches of each class. To understand the structural features required for in-silico designing of next-generation PARP1 inhibitors, we also reported the crucial amino acid interactions of these inhibitors at the target site. Thus, present review provides the insight on recent development on new lead structures as PARP1 inhibitors, their SAR, an overview of in-vitro and in-vivo screening methods, current challenges and opinion on future designing of more selective and safe PARP1 inhibitors.
|
Inhibition of PARP2 (unknown origin)
|
Homo sapiens
|
2.1
nM
|
|
Inhibition of PARP2 (unknown origin)
|
Homo sapiens
|
4.0
nM
|
|
Journal : Eur J Med Chem
Title : Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update.
Year : 2019
Volume : 165
First Page : 198
Last Page : 215
Authors : Jain PG, Patel BD.
Abstract : Poly (ADP-ribose) Polymerase1 (PARP1) is a member of 17 membered PARP family having diversified biological functions such as synthetic lethality, DNA repair, apoptosis, necrosis, histone binding etc. It is primarily a chromatin-bound nuclear enzyme that gets activated by DNA damage. It binds to DNA signal- and double-strand breaks, does parylation of target proteins (using NAD+ as a substrate) like histones and other DNA repair proteins and modifies them as a part of DNA repair mechanism. Inhibition of PARP1 prevents the DNA repair and leads to cell death. Clinically, PARP1 Inhibitors have shown their potential in treating BRCAm breast and ovarian cancers and trials are going on for the treatment of other solid tumors like pancreatic, prostate, colorectal etc. as a single agent or in combination. There are currently three FDA approved PARP1 inhibitors namely Olaparib, Rucaparib and Niraparib in the market while Veliparib and Talazoparib are in the late stage of clinical development. All these molecules are nonselective PARP1 inhibitors with concurrent inhibition of PARP2 with similar potency. In addition, resistance to marketed PARP1 inhibitors has been reported. Overall, looking at the success rate of PARP1 inhibitors into various solid tumors, there is an urge of a novel and selective PARP1 inhibitors. This review provides an update on various newer heterocyclic PARP1 inhibitors reported in last three years along with their structural design strategies. We classified them into two main chemical classes; NAD analogues and non-NAD analogues and discussed the medicinal chemistry approaches of each class. To understand the structural features required for in-silico designing of next-generation PARP1 inhibitors, we also reported the crucial amino acid interactions of these inhibitors at the target site. Thus, present review provides the insight on recent development on new lead structures as PARP1 inhibitors, their SAR, an overview of in-vitro and in-vivo screening methods, current challenges and opinion on future designing of more selective and safe PARP1 inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
42.76
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
31.76
%
|
|
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
|
0.21
%
|
|
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
|
0.2
%
|
|
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
|
0.2
%
|
|
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
|
0.21
%
|
|
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.
