The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptoti...The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family 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（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, 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.展开更多
基金financially supported by Postdoctoral Applied Research Project of Qingdao(No.861605040085,to CZ,SW)Grant of Innovation Plan in Biomedical Research of Qingdao City(No.15-10-3-15-(28)-zch,to SW)
文摘The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family 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（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, 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.
