2. Academic Validation
  3. Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties

Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties

  • Eur J Med Chem. 2023 Feb 15;248:115076. doi: 10.1016/j.ejmech.2022.115076.
Zhenwei Zhang 1,  Shan Zhao 1,  Jiying Pei 1,  Linghui Hou 1,  Shenglin Luan 2,  Hongguang Deng 1,  Dan Liu 1,  Min Huang 3,  Linxiang Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 China Resources Sanjiu Medical & Pharmaceutical Co., Ltd., Shenzhen, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 36680883 DOI: 10.1016/j.ejmech.2022.115076
Abstract

Direct activation of the pro-apoptotic protein Bax represents a potential therapeutic strategy to trigger Apoptosis in Cancer. Herein, structural optimization of the reported Bax trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and Apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the Bax activation cascade, promoting Bax insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and Apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent Bax trigger site activators for the treatment of BAX-expressing malignancies.

Keywords

Anti-tumor agents; Apoptosis; BAX; Trigger site.

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