|
The compound was tested for inhibitory activity against Aldose reductase from human placenta
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Gossypol and derivatives: a new class of aldose reductase inhibitors.
Year : 1991
Volume : 34
Issue : 11
First Page : 3301
Last Page : 3305
Authors : Deck LM, Vander Jagt DL, Royer RE.
Abstract : Gossypol and 17 derivatives were tested as inhibitors of aldose reductase from human placenta. Gossypol and a number of the derivatives were potent inhibitors. The order of inhibitory activity was interpreted in relation to the Kador-Sharpless pharmacophor model for the aldose reductase inhibitor site. The structural but not the electronic aspects of the model were found to apply to this series of compounds.
|
Inhibitory concentration against Bcl-xl
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins.
Year : 2003
Volume : 46
Issue : 20
First Page : 4259
Last Page : 4264
Authors : Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M.
Abstract : Among the most promising chemopreventive agents, certain natural polyphenols have recently received a great deal of attention because of their demonstrated inhibitory activity against tumorigenesis. In view of their anticancer properties, these compounds also hold great promise as potential chemotherapeutic agents. However, to translate these chemopreventive agents into chemotherapeutic compounds, their exact mechanisms of action must be delineated. By using a multidisciplinary approach guided by modern nuclear magnetic resonance spectroscopy techniques, fluorescence polarization displacement assays, and cell-based assays, we have begun to unravel the mechanisms of actions of certain polyphenols such as Gossypol (a compound from cotton seed extracts) and Purpurogallin (a natural compound extracted from Quercus sp. nutgall) and their derivatives. Our findings suggest that these natural products bind and antagonize the antiapoptotic effects of B-cell lymphocyte/leukemia-2 (Bcl-2) family proteins such as Bcl-x(L). Our in vitro and in vivo data not only open a window of opportunities for the development of novel cancer treatments with these compounds but also provide structural information that can be used for the design and development of novel and more effective analogues.
|
Displacement of FAM-Bid from human Bcl2 by FP assay
|
Homo sapiens
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Year : 2006
Volume : 49
Issue : 21
First Page : 6139
Last Page : 6142
Authors : Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S.
Abstract : A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.
|
Binding affinity to human Bcl2 by ELISA
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Year : 2006
Volume : 49
Issue : 21
First Page : 6139
Last Page : 6142
Authors : Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S.
Abstract : A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.
|
Displacement of FAM-Bak from human Bcl-xL by FP assay
|
Homo sapiens
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Year : 2006
Volume : 49
Issue : 21
First Page : 6139
Last Page : 6142
Authors : Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S.
Abstract : A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.
|
Displacement of FAM-Bid from human Mcl1 by FP assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Year : 2006
Volume : 49
Issue : 21
First Page : 6139
Last Page : 6142
Authors : Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S.
Abstract : A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.
|
Displacement of FAM-Bim peptide from human Bcl2 by fluorescence polarization assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the anti-apoptotic Bcl-2 proteins.
Year : 2007
Volume : 50
Issue : 14
First Page : 3163
Last Page : 3166
Authors : Tang G, Ding K, Ding K, Nikolovska-Coleska Z, Yang CY, Qiu S, Shangary S, Wang R, Guo J, Gao W, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Wang S.
Abstract : Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-231 breast cancer cell line with an IC50 value of 110 nM and effectively induces apoptosis.
|
Displacement of FAM-Bim peptide from human Mcl1 by fluorescence polarization assay
|
Homo sapiens
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the anti-apoptotic Bcl-2 proteins.
Year : 2007
Volume : 50
Issue : 14
First Page : 3163
Last Page : 3166
Authors : Tang G, Ding K, Ding K, Nikolovska-Coleska Z, Yang CY, Qiu S, Shangary S, Wang R, Guo J, Gao W, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Wang S.
Abstract : Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-231 breast cancer cell line with an IC50 value of 110 nM and effectively induces apoptosis.
|
Binding affinity to BCL2
|
None
|
467.74
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
Year : 2007
Volume : 104
Issue : 49
First Page : 19512
Last Page : 19517
Authors : Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Bélec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC.
Abstract : Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.
|
Cytotoxicity against human HeLa cells by SRB assay
|
Homo sapiens
|
0.08
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic and antibacterial sesquiterpenes from Thespesia populnea.
Year : 2008
Volume : 71
Issue : 7
First Page : 1173
Last Page : 1177
Authors : Boonsri S, Karalai C, Ponglimanont C, Chantrapromma S, Kanjana-Opas A.
Abstract : Eight new sesquiterpenoids, named populene A-H (1-8), were isolated from dichloromethane extracts of the wood and dark heartwood of Thespesia populnea, together with 11 known compounds (9-19). Their structures were determined on the basis of spectroscopic analyses. The cytotoxic activity of isolated compounds was evaluated against four cancer cell lines: MCF-7, HeLa, HT-29, and KB. Mansonone E (11) and (+)-gossypol (18) showed significant activities. Their antibacterial properties against Bacillus subtilis, Staphylococcus aureus, and Enterococcus faecalis are also presented.
|
Cytotoxicity against human HT29 cells by SRB assay
|
Homo sapiens
|
5.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic and antibacterial sesquiterpenes from Thespesia populnea.
Year : 2008
Volume : 71
Issue : 7
First Page : 1173
Last Page : 1177
Authors : Boonsri S, Karalai C, Ponglimanont C, Chantrapromma S, Kanjana-Opas A.
Abstract : Eight new sesquiterpenoids, named populene A-H (1-8), were isolated from dichloromethane extracts of the wood and dark heartwood of Thespesia populnea, together with 11 known compounds (9-19). Their structures were determined on the basis of spectroscopic analyses. The cytotoxic activity of isolated compounds was evaluated against four cancer cell lines: MCF-7, HeLa, HT-29, and KB. Mansonone E (11) and (+)-gossypol (18) showed significant activities. Their antibacterial properties against Bacillus subtilis, Staphylococcus aureus, and Enterococcus faecalis are also presented.
|
Cytotoxicity against human KB cells by SRB assay
|
Homo sapiens
|
0.04
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Cytotoxic and antibacterial sesquiterpenes from Thespesia populnea.
Year : 2008
Volume : 71
Issue : 7
First Page : 1173
Last Page : 1177
Authors : Boonsri S, Karalai C, Ponglimanont C, Chantrapromma S, Kanjana-Opas A.
Abstract : Eight new sesquiterpenoids, named populene A-H (1-8), were isolated from dichloromethane extracts of the wood and dark heartwood of Thespesia populnea, together with 11 known compounds (9-19). Their structures were determined on the basis of spectroscopic analyses. The cytotoxic activity of isolated compounds was evaluated against four cancer cell lines: MCF-7, HeLa, HT-29, and KB. Mansonone E (11) and (+)-gossypol (18) showed significant activities. Their antibacterial properties against Bacillus subtilis, Staphylococcus aureus, and Enterococcus faecalis are also presented.
|
Inhibition of Bcl-xL
|
None
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Fragment-based deconstruction of Bcl-xL inhibitors.
Year : 2010
Volume : 53
Issue : 6
First Page : 2577
Last Page : 2588
Authors : Barelier S, Pons J, Marcillat O, Lancelin JM, Krimm I.
Abstract : Fragment-based drug design consists of screening low-molecular-weight compounds in order to identify low-affinity ligands that are then modified or linked to yield potent inhibitors. The method thus attempts to build bioactive molecules in a modular way and relies on the hypothesis that the fragment binding mode will be conserved upon elaboration of the active molecule. If the inverse process is considered, do the fragments resulting from the deconstruction of high-affinity inhibitors recapitulate their binding mode in the large molecule? Few studies deal with this issue. Here, we report the analysis of 22 fragments resulting from the dissection of 9 inhibitors of the antiapoptotic protein Bcl-x(L). To determine if the fragments retained affinity toward the protein and identify their binding site, ligand-observed and protein-observed NMR experiments were used. The analysis of the fragments behavior illustrates the complexity of low-affinity protein-ligand interactions involved in the fragment-based construction of bioactive molecules.
|
Displacement of FITC-labeled Bak BH3 peptide from Bcl-XL after 30 mins by fluorescence polarization assay
|
None
|
540.0
nM
|
|
Displacement of FITC-labeled Bak BH3 peptide from Bcl-XL after 30 mins by fluorescence polarization assay
|
None
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins.
Year : 2010
Volume : 53
Issue : 10
First Page : 4166
Last Page : 4176
Authors : Wei J, Stebbins JL, Kitada S, Dash R, Placzek W, Rega MF, Wu B, Cellitti J, Zhai D, Yang L, Dahl R, Fisher PB, Reed JC, Pellecchia M.
Abstract : In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here the synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 0.31, 0.32, 0.20, and 0.62 microM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC(50) values of 0.13, 0.56, and 0.049 microM, respectively, and shows little cytotoxicity against bax(-/-)bak(-/-) cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.
|
Displacement of FITC-labeled Bak BH3 peptide from Bcl-2 after 30 mins by fluorescence polarization assay
|
None
|
300.0
nM
|
|
Displacement of FITC-labeled Bak BH3 peptide from Bcl-2 after 30 mins by fluorescence polarization assay
|
None
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins.
Year : 2010
Volume : 53
Issue : 10
First Page : 4166
Last Page : 4176
Authors : Wei J, Stebbins JL, Kitada S, Dash R, Placzek W, Rega MF, Wu B, Cellitti J, Zhai D, Yang L, Dahl R, Fisher PB, Reed JC, Pellecchia M.
Abstract : In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here the synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 0.31, 0.32, 0.20, and 0.62 microM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC(50) values of 0.13, 0.56, and 0.049 microM, respectively, and shows little cytotoxicity against bax(-/-)bak(-/-) cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.
|
Binding affinity to Bcl-xl
|
None
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
Binding affinity to BCl2
|
None
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
Binding affinity to MCL1
|
None
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
Inhibition of HIV1 reverse transcriptase activity at 20 ug/ml
|
Human immunodeficiency virus 1
|
73.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activities of novel gossypol derivatives.
Year : 2012
Volume : 22
Issue : 3
First Page : 1415
Last Page : 1420
Authors : Yang J, Zhang F, Li J, Chen G, Wu S, Ouyang W, Pan W, Yu R, Yang J, Tien P.
Abstract : In this study, a series of novel gossypol derivatives were synthesized and screened in vitro for their anti-HIV-1 and anti-H(5)N(1) activities, respectively. Replacing the aldehyde groups of gossypol with some amino acids not only reduced the cytotoxicity but also enhanced the activities against HIV-1 and H(5)N(1). Compounds 13-17 showed more potent activities against HIV-1 and H(5)N(1) than the other gossypol derivatives. Meanwhile, these compounds also exhibited more potent activities against H(5)N(1) than 1-adamantylamine. The absence of the COONa group in gossypol derivatives resulted in a loss of anti-HIV-1 activity, suggesting that this group might play an important role in mediating the antiviral activity. Time-of-addition assays indicated that compounds 13-17 had the similar mechanism of anti-HIV-1 action with T20. Molecular modeling analysis demonstrated that compounds 13-17 could fit inside the gp41 hydrophobic pocket through hydrogen bonding network, hydrophobic contacts and strong electrostatic interactions.
|
Inhibition of HIV1 reverse transcriptase activity at 4 ug/ml
|
Human immunodeficiency virus 1
|
76.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activities of novel gossypol derivatives.
Year : 2012
Volume : 22
Issue : 3
First Page : 1415
Last Page : 1420
Authors : Yang J, Zhang F, Li J, Chen G, Wu S, Ouyang W, Pan W, Yu R, Yang J, Tien P.
Abstract : In this study, a series of novel gossypol derivatives were synthesized and screened in vitro for their anti-HIV-1 and anti-H(5)N(1) activities, respectively. Replacing the aldehyde groups of gossypol with some amino acids not only reduced the cytotoxicity but also enhanced the activities against HIV-1 and H(5)N(1). Compounds 13-17 showed more potent activities against HIV-1 and H(5)N(1) than the other gossypol derivatives. Meanwhile, these compounds also exhibited more potent activities against H(5)N(1) than 1-adamantylamine. The absence of the COONa group in gossypol derivatives resulted in a loss of anti-HIV-1 activity, suggesting that this group might play an important role in mediating the antiviral activity. Time-of-addition assays indicated that compounds 13-17 had the similar mechanism of anti-HIV-1 action with T20. Molecular modeling analysis demonstrated that compounds 13-17 could fit inside the gp41 hydrophobic pocket through hydrogen bonding network, hydrophobic contacts and strong electrostatic interactions.
|
Antiproliferative activity against human HepG2 cells after 48 hrs by MTT assay
|
Homo sapiens
|
10.16
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein.
Year : 2012
Volume : 20
Issue : 14
First Page : 4194
Last Page : 4200
Authors : Li HQ, Yang J, Ma S, Qiao C.
Abstract : A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
|
Antiproliferative activity against human PC3 cells after 48 hrs by MTT assay
|
Homo sapiens
|
6.71
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein.
Year : 2012
Volume : 20
Issue : 14
First Page : 4194
Last Page : 4200
Authors : Li HQ, Yang J, Ma S, Qiao C.
Abstract : A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
|
Antiproliferative activity against mouse B16/F10 cells after 48 hrs by MTT assay
|
Mus musculus
|
5.56
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein.
Year : 2012
Volume : 20
Issue : 14
First Page : 4194
Last Page : 4200
Authors : Li HQ, Yang J, Ma S, Qiao C.
Abstract : A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
|
Inhibition of FAM-Bak-BH3 binding to human N-terminal His6-tagged Bcl2 isoform 2 after 4 hrs by fluorescence polarization assay
|
Homo sapiens
|
334.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein.
Year : 2012
Volume : 20
Issue : 14
First Page : 4194
Last Page : 4200
Authors : Li HQ, Yang J, Ma S, Qiao C.
Abstract : A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
-12.38
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
-2.11
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Antiamoebic activity against Entamoeba histolytica
|
Entamoeba histolytica
|
0.00777
ug.mL-1
|
|
Journal : Med Chem Res
Title : Exploring QSAR of antiamoebic agents of isolated natural products by MLR, ANN, and RTO
Year : 2012
Volume : 21
Issue : 9
First Page : 2501
Last Page : 2516
Authors : Ramirez-Galicia G, Martinez-Pacheco H, Garduno-Juarez R, Deeb O
|
Inhibition of biotin-Bim peptide binding to Mcl1 (unknown origin) expressed in Escherichia coli BL21 by ELISA
|
Homo sapiens
|
213.8
nM
|
|
Inhibition of biotin-Bim peptide binding to Mcl1 (unknown origin) expressed in Escherichia coli BL21 by ELISA
|
Homo sapiens
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors.
Year : 2013
Volume : 60
First Page : 410
Last Page : 420
Authors : Zhang Z, Liu C, Li X, Song T, Wu Z, Liang X, Zhao Y, Shen X, Chen H.
Abstract : We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1.
|
Inhibition of FAM-Bid peptide binding to Mcl1 (unknown origin) expressed in Escherichia coli BL21 by fluorescence polarization-based binding assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors.
Year : 2013
Volume : 60
First Page : 410
Last Page : 420
Authors : Zhang Z, Liu C, Li X, Song T, Wu Z, Liang X, Zhao Y, Shen X, Chen H.
Abstract : We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1.
|
Displacement of FAM-Bid BH3 peptide from recombinant Bcl-2 (unknown origin) expressed in Escherichia coli BL21 after 10 mins by fluorescence polarization assay
|
Homo sapiens
|
558.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and application of a rigid quinazolone scaffold based on two-face Bim α-helix mimicking.
Year : 2013
Volume : 69
First Page : 711
Last Page : 718
Authors : Zhang Z, Liang X, Li X, Song T, Chen Q, Sheng H.
Abstract : Based on our previous discovery of an anthraquinone scaffold mimicking two faces of Bim α-helix, we derived a quinazolone scaffold through structure simplification and optimization. It was inferred that a rigid bicyclic ring was necessary and efficient to maintain the two-faced binding mode. A novel dual inhibitor 6c [6,7,8-trihydroxy-3-(2-hydroxy-5-methylbenzyl)-2-phenylquinazolin-4(3H)-one] was obtained based on this scaffold. 6c exhibited dual binding activity with K(i) values of 0.123 μM for Mcl-1 and 0.179 μM for Bcl-2.
|
Displacement of FAM-Bid BH3 peptide from recombinant Mcl-1 (unknown origin) expressed in Escherichia coli BL21 after 10 mins by fluorescence polarization assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and application of a rigid quinazolone scaffold based on two-face Bim α-helix mimicking.
Year : 2013
Volume : 69
First Page : 711
Last Page : 718
Authors : Zhang Z, Liang X, Li X, Song T, Chen Q, Sheng H.
Abstract : Based on our previous discovery of an anthraquinone scaffold mimicking two faces of Bim α-helix, we derived a quinazolone scaffold through structure simplification and optimization. It was inferred that a rigid bicyclic ring was necessary and efficient to maintain the two-faced binding mode. A novel dual inhibitor 6c [6,7,8-trihydroxy-3-(2-hydroxy-5-methylbenzyl)-2-phenylquinazolin-4(3H)-one] was obtained based on this scaffold. 6c exhibited dual binding activity with K(i) values of 0.123 μM for Mcl-1 and 0.179 μM for Bcl-2.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
24.45
%
|
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
68.48
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
58.3
%
|
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
15.81
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of Bcl-2 (unknown origin) using 5-FAM-Bid-BH3 as substrate preincubated for 30 mins before substrate addition measured after 20 mins by fluorescence polarization technique
|
Homo sapiens
|
620.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary bioactivity studies of 2-thioxo-4-thiazolidinone derivatives as Bcl-2 inhibitors.
Year : 2015
Volume : 23
Issue : 9
First Page : 1994
Last Page : 2003
Authors : Wan Y, Wu S, Xiao G, Liu T, Hou X, Chen C, Guan P, Yang X, Fang H.
Abstract : The B-cell lymphoma-2 (Bcl-2) protein is a promising target for cancer therapy. In the present study, a series of 2-thioxo-4-thiazolidinone derivatives were designed and synthesized as Bcl-2 inhibitors. Most of them possessed decent inhibitory activity for anti-apoptotic Bcl-2 proteins. Among them, compound 31 has similar growth inhibition towards K562 compared to (R)-Gossypol. In addition, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 74 nM.
|
PubChem BioAssay. SW480 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
956.3
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. RKO viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
915.6
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. HCT116 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
784.4
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. SNU-C1 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
353.8
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. DLD-1 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
834.5
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of Bcl-xL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
640.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of 3-aryl-rhodanine benzoic acids as anti-apoptotic protein Bcl-2 inhibitors.
Year : 2015
Volume : 25
Issue : 22
First Page : 5265
Last Page : 5269
Authors : Fu H, Hou X, Wang L, Dun Y, Yang X, Fang H.
Abstract : A new class of 3-aryl-rhodanine benzoic acid derivatives were designed, synthesized, and evaluated for their inhibition activities against anti-apoptotic Bcl-2 proteins. The potent compounds 33 and 41 bound to Bcl-2 with submicromolar Ki values and had selectivities to Bcl-2/Mcl-1 over Bcl-xL. In addition, they exhibited obvious antiproliferative activities in three human tumor cell lines (MDA-MB-231, K562 and PC-3).
|
Inhibition of Mcl-1 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
310.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of 3-aryl-rhodanine benzoic acids as anti-apoptotic protein Bcl-2 inhibitors.
Year : 2015
Volume : 25
Issue : 22
First Page : 5265
Last Page : 5269
Authors : Fu H, Hou X, Wang L, Dun Y, Yang X, Fang H.
Abstract : A new class of 3-aryl-rhodanine benzoic acid derivatives were designed, synthesized, and evaluated for their inhibition activities against anti-apoptotic Bcl-2 proteins. The potent compounds 33 and 41 bound to Bcl-2 with submicromolar Ki values and had selectivities to Bcl-2/Mcl-1 over Bcl-xL. In addition, they exhibited obvious antiproliferative activities in three human tumor cell lines (MDA-MB-231, K562 and PC-3).
|
Competitive binding affinity to Mcl-1 (unknown origin) using 5-FAM-Bid-BH3 peptide preincubated for 30 mins before 5-FAM-Bid-BH3 peptide addition and measured 20 mins after 5-FAM-Bid-BH3 peptide addition by fluorescence polarization assay
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors.
Year : 2015
Volume : 23
Issue : 24
First Page : 7685
Last Page : 7693
Authors : Wan Y, Wang J, Sun F, Chen M, Hou X, Fang H.
Abstract : Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki=0.53μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki=0.39μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.
|
Competitive binding affinity to Bcl-XL (unknown origin) using 5-FAM-Bid-BH3 peptide preincubated for 30 mins before 5-FAM-Bid-BH3 peptide addition and measured 20 mins after 5-FAM-Bid-BH3 peptide addition by fluorescence polarization assayy
|
Homo sapiens
|
770.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors.
Year : 2015
Volume : 23
Issue : 24
First Page : 7685
Last Page : 7693
Authors : Wan Y, Wang J, Sun F, Chen M, Hou X, Fang H.
Abstract : Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki=0.53μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki=0.39μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.
|
Competitive binding affinity to Bcl-2 (unknown origin) using 5-FAM-Bid-BH3 peptide preincubated for 30 mins before 5-FAM-Bid-BH3 peptide addition and measured 20 mins after 5-FAM-Bid-BH3 peptide addition by fluorescence polarization assay
|
Homo sapiens
|
560.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors.
Year : 2015
Volume : 23
Issue : 24
First Page : 7685
Last Page : 7693
Authors : Wan Y, Wang J, Sun F, Chen M, Hou X, Fang H.
Abstract : Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki=0.53μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki=0.39μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.
|
Displacement of FAM-Bid peptide from N-terminal 8x His-tagged MCl-1 (unknown origin) expressed in Escherichia coli BL21 (DE3) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics.
Year : 2016
Volume : 59
Issue : 7
First Page : 3152
Last Page : 3162
Authors : Wang Z, Song T, Feng Y, Guo Z, Fan Y, Xu W, Liu L, Wang A, Zhang Z.
Abstract : No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, we extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.
|
Displacement of FAM-Bid peptide from N-terminal 8x His-tagged Bcl-2 (unknown origin) expressed in Escherichia coli BL21 (DE3) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
431.0
nM
|
|
Journal : J. Med. Chem.
Title : Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics.
Year : 2016
Volume : 59
Issue : 7
First Page : 3152
Last Page : 3162
Authors : Wang Z, Song T, Feng Y, Guo Z, Fan Y, Xu W, Liu L, Wang A, Zhang Z.
Abstract : No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, we extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.
|
Inhibition of Bcl-2 (unknown origin) using FAM-Bid peptide as substrate at 50 uM by fluorescence polarization-based assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural modification of luteolin from Flos Chrysanthemi leads to increased tumor cell growth inhibitory activity.
Year : 2016
Volume : 26
Issue : 15
First Page : 3464
Last Page : 3467
Authors : Yang C, Chen H, Lu S, Zhang M, Tian W, Wang M, Zhang L, Song Y, Shen A, Zhou Y, Zhu J, Zheng C.
Abstract : The luteolin from Flos Chrysanthemi was found to directly bind to the Bcl-2 protein and inhibit the tumor cell growth in our previous study. However, it has been shown to possess wide and week biological activities. In this study, a series of derivatives of luteolin were designed and synthesized, and their tumor cell growth inhibitory activities were evaluated against human leukemia cell line HL-60. The results showed that compounds 1B-2, 2A-3, and 2B-5, with hydrophobic substituted benzyl groups introduced to B ring and hydrogen or methyl introduced to 7-OH group of luteolin, exhibited the strongest inhibitory activity with the IC50 lower than 10μM, which were significantly more potent than luteolin. The studies presented here offer a good example for modifications of flavones to improve their tumor cell growth inhibitory activities.
|
Inhibition of Bcl-2 (unknown origin) using FAM-Bid peptide as substrate by fluorescence polarization-based assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural modification of luteolin from Flos Chrysanthemi leads to increased tumor cell growth inhibitory activity.
Year : 2016
Volume : 26
Issue : 15
First Page : 3464
Last Page : 3467
Authors : Yang C, Chen H, Lu S, Zhang M, Tian W, Wang M, Zhang L, Song Y, Shen A, Zhou Y, Zhu J, Zheng C.
Abstract : The luteolin from Flos Chrysanthemi was found to directly bind to the Bcl-2 protein and inhibit the tumor cell growth in our previous study. However, it has been shown to possess wide and week biological activities. In this study, a series of derivatives of luteolin were designed and synthesized, and their tumor cell growth inhibitory activities were evaluated against human leukemia cell line HL-60. The results showed that compounds 1B-2, 2A-3, and 2B-5, with hydrophobic substituted benzyl groups introduced to B ring and hydrogen or methyl introduced to 7-OH group of luteolin, exhibited the strongest inhibitory activity with the IC50 lower than 10μM, which were significantly more potent than luteolin. The studies presented here offer a good example for modifications of flavones to improve their tumor cell growth inhibitory activities.
|
Inhibition of Bcl-XL (unknown origin) using FAM-Bid peptide as substrate at 50 uM by fluorescence polarization-based assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural modification of luteolin from Flos Chrysanthemi leads to increased tumor cell growth inhibitory activity.
Year : 2016
Volume : 26
Issue : 15
First Page : 3464
Last Page : 3467
Authors : Yang C, Chen H, Lu S, Zhang M, Tian W, Wang M, Zhang L, Song Y, Shen A, Zhou Y, Zhu J, Zheng C.
Abstract : The luteolin from Flos Chrysanthemi was found to directly bind to the Bcl-2 protein and inhibit the tumor cell growth in our previous study. However, it has been shown to possess wide and week biological activities. In this study, a series of derivatives of luteolin were designed and synthesized, and their tumor cell growth inhibitory activities were evaluated against human leukemia cell line HL-60. The results showed that compounds 1B-2, 2A-3, and 2B-5, with hydrophobic substituted benzyl groups introduced to B ring and hydrogen or methyl introduced to 7-OH group of luteolin, exhibited the strongest inhibitory activity with the IC50 lower than 10μM, which were significantly more potent than luteolin. The studies presented here offer a good example for modifications of flavones to improve their tumor cell growth inhibitory activities.
|
Inhibition of Bcl-XL (unknown origin) using FAM-Bid peptide as substrate by fluorescence polarization-based assay
|
Homo sapiens
|
310.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural modification of luteolin from Flos Chrysanthemi leads to increased tumor cell growth inhibitory activity.
Year : 2016
Volume : 26
Issue : 15
First Page : 3464
Last Page : 3467
Authors : Yang C, Chen H, Lu S, Zhang M, Tian W, Wang M, Zhang L, Song Y, Shen A, Zhou Y, Zhu J, Zheng C.
Abstract : The luteolin from Flos Chrysanthemi was found to directly bind to the Bcl-2 protein and inhibit the tumor cell growth in our previous study. However, it has been shown to possess wide and week biological activities. In this study, a series of derivatives of luteolin were designed and synthesized, and their tumor cell growth inhibitory activities were evaluated against human leukemia cell line HL-60. The results showed that compounds 1B-2, 2A-3, and 2B-5, with hydrophobic substituted benzyl groups introduced to B ring and hydrogen or methyl introduced to 7-OH group of luteolin, exhibited the strongest inhibitory activity with the IC50 lower than 10μM, which were significantly more potent than luteolin. The studies presented here offer a good example for modifications of flavones to improve their tumor cell growth inhibitory activities.
|
Inhibition of 5-FAM-Bid peptide binding to Bcl-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites.
Year : 2016
Volume : 26
Issue : 21
First Page : 5207
Last Page : 5211
Authors : Wang M, Tian W, Wang C, Lu S, Yang C, Wang J, Song Y, Zhou Y, Zhu J, Li Z, Zheng C.
Abstract : The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL (E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.
|
Inhibition of 5-FAM-Bid peptide binding to Bcl-XL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
310.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites.
Year : 2016
Volume : 26
Issue : 21
First Page : 5207
Last Page : 5211
Authors : Wang M, Tian W, Wang C, Lu S, Yang C, Wang J, Song Y, Zhou Y, Zhu J, Li Z, Zheng C.
Abstract : The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL (E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.
|
Inhibition of 5-FAM-Bid peptide binding to MCL-1 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
640.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites.
Year : 2016
Volume : 26
Issue : 21
First Page : 5207
Last Page : 5211
Authors : Wang M, Tian W, Wang C, Lu S, Yang C, Wang J, Song Y, Zhou Y, Zhu J, Li Z, Zheng C.
Abstract : The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL (E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.
|
Inhibition of FAM-Bid binding to human MCL1 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
856.0
nM
|
|
Inhibition of FAM-Bid binding to human MCL1 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
162.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins.
Year : 2016
Volume : 7
Issue : 12
First Page : 1185
Last Page : 1190
Authors : Lu Y, Wu S, Yue Y, He S, Li J, Tang J, Wang W, Zhou HB.
Abstract : A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
|
Inhibition of FAM-Bid binding to human BCL2 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
511.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins.
Year : 2016
Volume : 7
Issue : 12
First Page : 1185
Last Page : 1190
Authors : Lu Y, Wu S, Yue Y, He S, Li J, Tang J, Wang W, Zhou HB.
Abstract : A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
|
Inhibition of 5-FAM-QEDIIRNIARHLAQVGDSMDRSIPPG binding to Mcl-1 (unknown origin) preincubated for 30 mins followed by FAM-labeled peptide addition measured after 20 mins by fluorescence polarization assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : Bioorg Med Chem
Title : Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains.
Year : 2017
Volume : 25
Issue : 1
First Page : 138
Last Page : 152
Authors : Wan Y, Liu T, Li X, Chen C, Fang H.
Abstract : As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki=0.077μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki=0.18μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki=8.45μM), which was the same as positive control Gossypol (Ki=7.54μM).
|
Inhibition of 5-FAM-QEDIIRNIARHLAQVGDSMDRSIPPG binding to Bcl-2 (unknown origin) preincubated for 30 mins followed by FAM-labeled peptide addition measured after 20 mins by fluorescence polarization assay
|
Homo sapiens
|
450.0
nM
|
|
Journal : Bioorg Med Chem
Title : Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains.
Year : 2017
Volume : 25
Issue : 1
First Page : 138
Last Page : 152
Authors : Wan Y, Liu T, Li X, Chen C, Fang H.
Abstract : As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki=0.077μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki=0.18μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki=8.45μM), which was the same as positive control Gossypol (Ki=7.54μM).
|
Inhibition of biotinylated Bim peptide binding to His-tagged Bcl-2 (unknown origin) preincubated for 1 hr followed by biotinylated Bim peptide addition measured after 2 hrs by ELISA
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents.
Year : 2017
Volume : 27
Issue : 4
First Page : 1037
Last Page : 1040
Authors : Hamdy R, Ziedan NI, Ali S, Bordoni C, El-Sadek M, Lashin E, Brancale A, Jones AT, Westwell AD.
Abstract : A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.
|
Inhibition of 6-carboxyfluorescein succinimidyl ester fluorescence tagged-Bid BH3 peptide (79 to 99 residues) binding to Bcl-2 (unknown origin) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
420.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1943
Last Page : 1948
Authors : Luan S, Ge Q, Chen Y, Dai M, Yang J, Li K, Liu D, Zhao L.
Abstract : Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.
|
Inhibition of 6-carboxyfluorescein succinimidyl ester fluorescence tagged-Bid BH3 peptide (79 to 99 residues) binding to Mcl-1 (unknown origin) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors.
Year : 2017
Volume : 27
Issue : 9
First Page : 1943
Last Page : 1948
Authors : Luan S, Ge Q, Chen Y, Dai M, Yang J, Li K, Liu D, Zhao L.
Abstract : Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.
|
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
|
66.34
%
|
|
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.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coliDH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured soluble pig heart MDH refolding by measuring MDH enzyme activity using sodium mesoxalate as substrate after 20 to 40 mins by malachite green dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
97.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coli DH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured rhodanese refolding by measuring rhodanese enzyme activity after 45 mins by Fe(SCN)3 dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
93.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Bcl2 (unknown origin)
|
Homo sapiens
|
320.0
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
Inhibition of Bcl-xL (unknown origin)
|
Homo sapiens
|
480.0
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
Inhibition of MCl-1 (unknown origin)
|
Homo sapiens
|
180.0
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
Inhibition of Pseudomonas aeruginosa IMPDH at 35.1 uM using IMP as substrate in the presence of NAD+ incubated for 70 secs relative to control
|
Pseudomonas aeruginosa
|
100.0
%
|
|
Journal : Eur J Med Chem
Title : First-in-class allosteric inhibitors of bacterial IMPDHs.
Year : 2019
Volume : 167
First Page : 124
Last Page : 132
Authors : Alexandre T, Lupan A, Helynck O, Vichier-Guerre S, Dugué L, Gelin M, Haouz A, Labesse G, Munier-Lehmann H.
Abstract : Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now.
|
Inhibition of Pseudomonas aeruginosa IMPDH using IMP as substrate in the presence of NAD+ incubated for 70 secs
|
Pseudomonas aeruginosa
|
900.0
nM
|
|
Journal : Eur J Med Chem
Title : First-in-class allosteric inhibitors of bacterial IMPDHs.
Year : 2019
Volume : 167
First Page : 124
Last Page : 132
Authors : Alexandre T, Lupan A, Helynck O, Vichier-Guerre S, Dugué L, Gelin M, Haouz A, Labesse G, Munier-Lehmann H.
Abstract : Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.02
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.739
%
|
|
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
|
7.89
%
|
|
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
|
6.48
%
|
|
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
|
6.48
%
|
|
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
|
7.89
%
|
|
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 N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) at 20uM using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
101.2
%
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with high 200 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and high 20 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
260.0
nM
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using high 10 uM hFX-CP as substrate mixture with 10 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
330.0
nM
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Displacement of FAM-Bid peptide from recombinant N-terminal His6x-tagged human Mcl-1 expressed in Escherichia coli BL21 (DE3) incubated for 30 mins by fluorescence polarization assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment.
Year : 2021
Volume : 29
First Page : 115851
Last Page : 115851
Authors : Xia YL,Wang JJ,Li SY,Liu Y,Gonzalez FJ,Wang P,Ge GB
Abstract : Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (K = 0.21 ± 0.02 μM, IC = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.
|
Inhibition of FAM-conjugated ssDNA binding to His-tagged wild type RAD52 (unknown origin) expressed in Rosetta2(DE3)/pLysS cells measured after 30 mins by high-throughput fluorescence polarization assay relative to control
|
Homo sapiens
|
60.0
%
|
|
Journal : J Med Chem
Title : Synthetic Lethality through the Lens of Medicinal Chemistry.
Year : 2020
Volume : 63
Issue : 23.0
First Page : 14151
Last Page : 14183
Authors : Myers SH,Ortega JA,Cavalli A
Abstract : Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.
|
Binding affinity to Mc1-1 (unknown origin) by fluorescence polarization competition assay
|
Homo sapiens
|
180.0
nM
|
|
|
Binding affinity to Bcl-2 (unknown origin) by fluorescence polarization competition assay
|
Homo sapiens
|
460.0
nM
|
|
|
Binding affinity to Bc1-xL (unknown origin) by fluorescence polarization competition assay
|
Homo sapiens
|
610.0
nM
|
|
|
Disruption of interaction between human recombinant GST-tagged MKK3/VF-tagged MYC expressed in HEK293T cells at 20 uM measured after 2 hrs by TR-FRET assay
|
Homo sapiens
|
31.0
%
|
|
|
Inhibition of porcine heart malate dehydrogenase preincubated for 5 min followed by nicotinamide adenine dinucleotide addition and monitered for 90 sec by spectrophotometric method
|
Sus scrofa
|
820.0
nM
|
|
