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

Xuexin Feng; Ziqin Yan; Feilong Zhou; Jianfeng Lou; Xilin Lyu; Xuelian Ren; Ziyu Zeng; Chenglong Liu; Shiyan Zhang; Di Zhu; He Huang; Jinming Yang; Yujun Zhao

doi:10.1016/j.ejmech.2022.114327

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

Eur J Med Chem. 2022 Jun 5:236:114327. doi: 10.1016/j.ejmech.2022.114327. Epub 2022 Mar 29.

Authors

Xuexin Feng¹, Ziqin Yan², Feilong Zhou², Jianfeng Lou³, Xilin Lyu², Xuelian Ren², Ziyu Zeng², Chenglong Liu⁴, Shiyan Zhang³, Di Zhu⁴, He Huang³, Jinming Yang⁵, Yujun Zhao⁶

Affiliations

¹ School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu, 224007, China; State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China.
² State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China.
³ State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
⁴ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 201203, China; Shanghai Engineering Research Center of Immune Therapy and Key Laboratory of Smart Drug Delivery, School of Pharmacy, Fudan University, Shanghai, 201203, China.
⁵ School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu, 224007, China. Electronic address: yangjm@yctu.edu.cn.
⁶ State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China. Electronic address: yjzhao@simm.ac.cn.

PMID: 35385805
DOI: 10.1016/j.ejmech.2022.114327

Abstract

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.

Keywords: Apoptosis; BCL-2; BFL-1; Covalent inhibitor; Cytochrome c; Protein-Protein interaction.

MeSH terms

Apoptosis
Methylcellulose / metabolism
Minor Histocompatibility Antigens / metabolism
Mitochondria / metabolism
Neoplasms* / metabolism
Proto-Oncogene Proteins c-bcl-2* / metabolism

Substances

Minor Histocompatibility Antigens
Proto-Oncogene Proteins c-bcl-2
Methylcellulose