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Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1

文献类型：期刊论文

作者Lou, Jianfeng7,8; Zhou, Qianqian6,7,8; Lyu, Xilin8; Cen, Xinyi5,7; Liu, Chen4,8; Yan, Ziqin8; Li, Yan8; Tang, Haotian3,8; Liu, Qiupei8; Ding, Jian6,7,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-06-24
页码36
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00291
通讯作者Huang, He(hhuang@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要Clinical and biological studies have shown that overexpression of BFL-1 is one contributing factor to venetoclax resistance. The resistance might be overcome by a potent BFL-1 inhibitor, but such an inhibitor is rare. In this study, we show that 56, featuring an acrylamide moiety, inhibited the BFL-1/BID interaction with a K-i value of 105 nM. More interestingly, 56 formed an irreversible conjugation adduct at the C55 residue of BFL-1. 56 was a selective BFL-1 inhibitor, and its MCL-1 binding affinity was 10-fold weaker, while it did not bind BCL-2 and BCL-xL. Mechanistic studies showed that 56 overcame venetoclax resistance in isogenic AML cell lines MOLM-13-OE and MV4-11-OE, which both overexpressed BFL-1. More importantly, 56 and venetoclax combination promoted stronger apoptosis induction than either single agent. Collectively, our data show that 56 overcame resistance to venetoclax in AML cells overexpressing BFL-1. These attributes make 56 a promising candidate for future optimization.
WOS关键词FLUORESCENCE POLARIZATION ASSAY ; ANTI-APOPTOTIC BCL-2 ; DUAL INHIBITORS ; FAMILY ; DESIGN ; PROTEINS ; MCL-1 ; IDENTIFICATION ; ABT-737 ; TARGET
资助项目Jinan Innovation Team Project[2021GXRC069] ; National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[82273759] ; National Natural Science Foundation of China[22277125] ; Innovative Research Institute by Department of Science and Technology of Guangdong Province[2021B0909050003] ; Science and Technology Commission of Shanghai Municipality[22ZR1474500] ; Science and Technology Commission of Shanghai Municipality[23ZR1474600]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001253345300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312053]  
专题新药研究国家重点实验室
通讯作者Huang, He; Xie, Hua; Zhao, Yujun
作者单位1.Ningxia Med Univ, Sch Pharm, Key Lab Protect, Dev & Utilizat Med Resources Liupanshan Area, Yinchuan 750004, Peoples R China
2.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lou, Jianfeng,Zhou, Qianqian,Lyu, Xilin,et al. Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:36.
APA Lou, Jianfeng.,Zhou, Qianqian.,Lyu, Xilin.,Cen, Xinyi.,Liu, Chen.,...&Zhao, Yujun.(2024).Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1.JOURNAL OF MEDICINAL CHEMISTRY,36.
MLA Lou, Jianfeng,et al."Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1".JOURNAL OF MEDICINAL CHEMISTRY (2024):36.

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来源：上海药物研究所

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