Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins
In: Journal of Medicinal Chemistry, Jg. 63 (2020-03-12), Heft 5, S. 2489-2510
serialPeriodical
Zugriff:
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 Kivalues of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24was 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.
Titel: |
Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins
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Autor/in / Beteiligte Person: | Kump, Karson J. ; Miao, Lei ; Mady, Ahmed S. A. ; Ansari, Nurul H. ; Shrestha, Uttar K. ; Yang, Yuting ; Pal, Mohan ; Liao, Chenzhong ; Perdih, Andrej ; Abulwerdi, Fardokht A. ; Chinnaswamy, Krishnapriya ; Meagher, Jennifer L. ; Carlson, Jacob M. ; Khanna, May ; Stuckey, Jeanne A. ; Nikolovska-Coleska, Zaneta |
Zeitschrift: | Journal of Medicinal Chemistry, Jg. 63 (2020-03-12), Heft 5, S. 2489-2510 |
Veröffentlichung: | 2020 |
Medientyp: | serialPeriodical |
ISSN: | 0022-2623 (print) ; 1520-4804 (print) |
DOI: | 10.1021/acs.jmedchem.9b01442 |
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