Open AccessDiscovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins
Author(s) -
Karson J. Kump,
Lei Miao,
Ahmed S.A. Mady,
Nurul H. Ansari,
Uttar K. Shrestha,
Yuting Yang,
M. Pal,
Chenzhong Liao,
Andrej Perdih,
Fardokht A. Abulwerdi,
Krishnapriya Chinnaswamy,
Jennifer L. Meagher,
Jacob M. Carlson,
May Khanna,
Jeanne A. Stuckey,
Zaneta NikolovskaColeska
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01442
Subject(s) - chemistry , apoptosis , benzoic acid , cocrystal , structure–activity relationship , lymphoma , cell culture , cancer research , cancer cell , combinatorial chemistry , computational biology , cancer , stereochemistry , biochemistry , in vitro , genetics , molecule , biology , immunology , hydrogen bond , organic chemistry
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 K i 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.