Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains.
As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki=0.077μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki=0.18μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki=8.45μM), which was the same as positive control Gossypol (Ki=7.54μM).
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
Yichao
Y
Wan
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
Tingting
T
Liu
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
Xiaoxian
X
Li
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
Chen
C
Chen
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China. Electronic address: haofangcn@sdu.edu.cn.
Hao
H
Fang
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006072:Gossypol / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D006072:Gossypol
Bcl-2; Cancer; Mcl-1; Pyrrolidine; Target