Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells
文献类型：期刊论文
| 作者 | Feng, Xuexin1,2,3; Yan, Ziqin2,3; Zhou, Feilong2,3; Lou, Jianfeng2,3,4; Lyu, Xilin2,3; Ren, Xuelian2,3; Zeng, Ziyu2,3; Liu, Chenglong5,6,7; Zhang, Shiyan2,3,4; Zhu, Di5,6,7 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-06-05 |
| 卷号 | 236页码:114327 |
| 关键词 | BFL-1 Apoptosis Covalent inhibitor Cytochrome c BCL-2 Protein-Protein interaction |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2022.114327 |
| 文献子类 | Article |
| 英文摘要 | 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. (C) 2022 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | FLUORESCENCE POLARIZATION ASSAY ; BCL-2 FAMILY ; CYTOCHROME-C ; RESISTANCE ; BINDING ; DESIGN ; BAK ; IDENTIFICATION ; ACTIVATION ; COMPLEX |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000821147500008 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309355]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Jinming; Zhao, Yujun |
| 作者单位 | 1.Yancheng Teachers Univ, Sch Pharm, Yancheng 224007, Jiangsu, Peoples R China; 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Small Mol Drug Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 5.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 201203, Peoples R China; 6.Fudan Univ, Shanghai Engn Res Ctr Immune Therapy, Sch Pharm, Shanghai 201203, Peoples R China; 7.Fudan Univ, Key Lab Smart Drug Delivery, Sch Pharm, Shanghai 201203, Peoples R China; 8.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China; 9.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China |
| 推荐引用方式 GB/T 7714 | Feng, Xuexin,Yan, Ziqin,Zhou, Feilong,et al. Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,236:114327. |
| APA | Feng, Xuexin.,Yan, Ziqin.,Zhou, Feilong.,Lou, Jianfeng.,Lyu, Xilin.,...&Zhao, Yujun.(2022).Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,236,114327. |
| MLA | Feng, Xuexin,et al."Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 236(2022):114327. |
入库方式： OAI收割
来源：上海药物研究所
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