期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 15, 页码 11330-11353出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00682
关键词
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资金
- National Natural Science Foundation of China [81930100, 81773581, 81773639]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZ202003]
- Qing Lan Project of Jiangsu Province
- Young Elite Scientists Sponsorship Program by CAST [YESS20180146]
- Double First Class Innovation Team of China Pharmaceutical University [CPU2018GY02]
The study describes the rational design, synthesis, and structure-activity relationships of Mcl-1 inhibitors. The most potent compound 40 showed high affinity and superior selectivity for Mcl-1, activating the apoptosis signal pathway in an Mcl1-dependent manner.
Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 mu M) led to the discovery of the most potent compound 40 with high affinity (K-d = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.
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