Citation: Zhang Chuan-Liang, Liu Shan, Liu Xiao-Chun, Gao Jiang-Ming, Wang Shu-Lin. Discovery of novel inhibitors of anti-apoptotic Bcl-2 proteins derived from Bim BH3 domain[J]. Chinese Chemical Letters, ;2017, 28(7): 1523-1527. doi: 10.1016/j.cclet.2017.03.010 shu

Discovery of novel inhibitors of anti-apoptotic Bcl-2 proteins derived from Bim BH3 domain

a.
School of Medicine and Pharmacy, Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao 266003, China
b.
Marine Biomedical Research Institute, Qingdao 266071, China

Corresponding author: Wang Shu-Lin, shulinwang@ouc.edu.cn
Received Date: 23 November 2016
Revised Date: 6 January 2017
Accepted Date: 7 March 2017
Available Online: 9 July 2017

Figures(3)

The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2 family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5 (K_D=9.48 nmol/L for Bcl-2) and SM-6 (K_D=0.08 nmol/L for Bcl-x_L), which exhibited improved binding affinity compared with the lead Bim (K_D=16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-x_L, respectively). These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.
- Apoptosis,
- Anti-apoptotic Bcl-2 proteins,
- Bim BH3 domain,
- Binding affinity,
- Anti-cancer activity
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