Design, synthesis and biological evaluation of dual Bcl-2/Mcl-1 inhibitors bearing 2-(1H-indol-4-yl)benzoic acid scaffold. (1st September 2021)

• Record Type: Journal Article
• Authors: Niu, Qun; Deng, Hongguang; Zhang, Zhenwei; Xu, Qinhao; Luan, Shenglin; Huang, Min; Liu, Dan; Zhao, Linxiang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 47(2021)
• Publication Date: 2021-09-01
• Subjects: Bcl-2/Mcl-1 -- Dual inhibitor -- Structure-based rational design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128215
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The anti-apoptotic protein inhibitors of the B cell lymphoma 2 (Bcl-2) family have been developed as new anticancer therapies. Numerous studies illustrated the great potential in the development of dual Bcl-2/myeloid cell leukemia 1 (Mcl-1) inhibitors. Herein, we reported a series of Bcl-2/Mcl-1 inhibitors that optimized from a hit compound 1 via structure-based rational design. The biological evaluation suggested that most compounds exhibited potent binding affinities at submicromolar to both Bcl-2 and Mcl-1 without any Bcl-xL binding affinities, especially compound 9o, with a K i value of 0.07 μM to Mcl-1 and 0.66 μM to Bcl-2, that has great potential for developing dual inhibitors targeting Bcl-2 and Mcl-1.