TY - JOUR
T1 - Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins
AU - Kump, Karson J.
AU - Miao, Lei
AU - Mady, Ahmed S.A.
AU - Ansari, Nurul H.
AU - Shrestha, Uttar K.
AU - Yang, Yuting
AU - Pal, Mohan
AU - Liao, Chenzhong
AU - Perdih, Andrej
AU - Abulwerdi, Fardokht A.
AU - Chinnaswamy, Krishnapriya
AU - Meagher, Jennifer L.
AU - Carlson, Jacob M.
AU - Khanna, May
AU - Stuckey, Jeanne A.
AU - Nikolovska-Coleska, Zaneta
N1 - Funding Information:
This work was supported by the NIH R01 CA-149442, CA-217141 and HL-13982401, R21 NS056915 grants, Harrington Discovery Award AACR Bayer Innovation and Discovery Award, and the MTRAC Fast Forward Medical Innovation Award to Z.N.-C.; NIH Training Program in Translational Research (T32-GM113900) and Rackham Merit Fellowship to K.J.K.; Advanced Proteome Informatics of Cancer (T32 CA140044) to A.S.A.M.; the bilateral research grant (BI/US/18-20-068) funded by the Slovenian Research Agency between the National Institute of Chemistry, Slovenia, and the University of Michigan, as well as the P1-0012 core research grant from Slovenian Research Agency funded the research visit of A.P. to the University of Michigan in the lab of Z.N.-C. Z.N.-C. and J.A.S. are grateful for the support of this work from NIH P30 CA046592. We kindly thank W. Clay Brown from the U-M Center for Structural Biology for providing expression vectors. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817).
Funding Information:
This work was supported by the NIH R01 CA-149442, CA-217141, and HL-13982401, R21 NS056915 grants, Harrington Discovery Award, AACR Bayer Innovation and Discovery Award, and the MTRAC Fast Forward Medical Innovation Award to Z.N.-C.; NIH Training Program in Translational Research (T32-GM113900) and Rackham Merit Fellowship to K.J.K.; Advanced Proteome Informatics of Cancer (T32 CA140044) to A.S.A.M.; the bilateral research grant (BI/US/18-20-068) funded by the Slovenian Research Agency between the National Institute of Chemistry, Slovenia, and the University of Michigan, as well as the P1-0012 core research grant from Slovenian Research Agency funded the research visit of A.P. to the University of Michigan in the lab of Z.N.-C. Z.N.-C. and J.A.S. are grateful for the support of this work from NIH P30 CA046592. We kindly thank W. Clay Brown from the U-M Center for Structural Biology for providing expression vectors. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817).
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/3/12
Y1 - 2020/3/12
N2 - Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.
AB - Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.
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U2 - 10.1021/acs.jmedchem.9b01442
DO - 10.1021/acs.jmedchem.9b01442
M3 - Article
C2 - 31971799
AN - SCOPUS:85081944613
SN - 0022-2623
VL - 63
SP - 2489
EP - 2510
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -