Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 3, Pages 1281-1297Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01659
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Funding
- National Natural Science Foundation of China [81573346, 81872737, 81773639, 81930100]
- Natural Science Foundation of Jiangsu Province of China [BK20190559]
- Double First Class Innovation Team of China Pharmaceutical University [CPU2018GY02]
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002, 2017ZX09302003, 2015ZX09101032]
- State Key Laboratory of Natural Medicines [SKLNMZZCX201803]
- China Postdoctoral Science Foundation [2018M642376]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-S936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (K-d = 0.5 mu M) and cellular inhibitory activity (IC50 = 1.73 mu M). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.
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