2. Academic Validation
  3. Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin

Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin

  • Eur J Med Chem. 2018 Nov 5:159:149-165. doi: 10.1016/j.ejmech.2018.09.059.
Xiaohua Liu 1,  Yu Zhang 2,  Wenjing Huang 2,  Jia Luo 2,  Yang Li 1,  Wenfu Tan 3,  Ao Zhang 4
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 3 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: wftan@fudan.edu.cn.
  • 4 CAS Key Laboratory of Receptor Research, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: aozhang@simm.ac.cn.
PMID: 30278333 DOI: 10.1016/j.ejmech.2018.09.059
Abstract

By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 Inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax.

Keywords

Apoptosis; Artemisinin; Bcl-2; Selectivity; Venetoclax.

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