Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein–Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy

Cheng, Jing; Yan, Ziqin; Jiang, Kailong; Liu, Chen; Xu, Dehua; Lyu, Xilin; Hu, Xiaobei; Zhang, Shiyan; Zhou, Yubo; Li, Jia; Zhao, Yujun

doi:10.1021/acs.jmedchem.3c01815

Cited by 6 publications

(1 citation statement)

References 83 publications

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“…The IC 50 values were calculated with GraphPad Prism. The K i values were calculated based on the equation K i = IC 50 /(1 + [L]/ K d ) following reported calculation methods. − …”

Section: Methodsmentioning

confidence: 99%

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

Lou,

Zhou,

Lyu

et al. 2024

J. Med. Chem.

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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.

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“…The IC 50 values were calculated with GraphPad Prism. The K i values were calculated based on the equation K i = IC 50 /(1 + [L]/ K d ) following reported calculation methods. − …”

Section: Methodsmentioning

confidence: 99%