2. Academic Validation
  3. Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1

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

  • J Med Chem. 2024 Jul 11;67(13):10795-10830. doi: 10.1021/acs.jmedchem.4c00291.
Jianfeng Lou 1 2,  Qianqian Zhou 3 1 2,  Xilin Lyu 1,  Xinyi Cen 2 4,  Chen Liu 1 5,  Ziqin Yan 1,  Yan Li 1,  Haotian Tang 1 6,  Qiupei Liu 1,  Jian Ding 3 1 2,  Ye Lu 1 5,  He Huang 3 2 4,  Hua Xie 3 1 2 6,  Yujun Zhao 1 2 5 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd. Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, PR China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 7 Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China.
  • 8 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
PMID: 38913996 DOI: 10.1021/acs.jmedchem.4c00291
Abstract

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 Ki 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.

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