Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells

• Published in: European journal of medicinal chemistry 2022-06, Vol.236, p.114327-114327, Article 114327
• Main Authors: Feng, Xuexin, Yan, Ziqin, Zhou, Feilong, Lou, Jianfeng, Lyu, Xilin, Ren, Xuelian, Zeng, Ziyu, Liu, Chenglong, Zhang, Shiyan, Zhu, Di, Huang, He, Yang, Jinming, Zhao, Yujun
• Format: Article
• Language: English
• Subjects: Apoptosis; BCL-2; BFL-1; Covalent inhibitor; Cytochrome c; Protein-Protein interaction
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114327

Induction of apoptosis by the FDA-approved drug Venetoclax in cancer cells mainly derives from blocking the interactions between BCL-2 and BH3-only proteins. Anti-apoptotic BFL-1, a homolog of BCL-2, also competitively binds to the BH3-only proteins and is responsible for Venetoclax-induced drug resistance. Compared to BCL-2, small-molecule inhibitors of BFL-1 are relatively underexplored. In order to tackle this issue, in-house compound library was screened and a hit compound was identified and optimized to obtain 12 (ZH97) functioning as a covalent and selective inhibitor of BFL-1. 12 modifies BFL-1 at the C55 residue, blocks BFL-1/BID interaction in vitro, promotes cellular cytochrome c release from mitochondria, and induced apoptosis in BFL-1 overexpressing cancer cells. Mechanistic studies show that 12 inhibited BFL-1/PUMA interaction in cell lysate and is effective in cancer cells that harboring high expression level of BFL-1. In summary, blockade of BFL-1/BH3-only proteins interactions with a covalent small-molecule inhibitor induced apoptosis and elicited antitumor activity. Thus, our study demonstrates an appealing strategy for selective modulation of cellular BFL-1 for cancer therapy. [Display omitted] •A selective and covalent small-molecule inhibitor of BFL-1, 12, has been discovered;•12 induced robust release of cytochrome c from mitochondria;•12 induced robust apoptosis of cancer cells overexpressing BFL-1;•12 blocked BFL-1/PUMA interaction in living cells.