Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer
- J Med Chem. 2020 Feb 13;63(3):1281-1297. doi: 10.1021/acs.jmedchem.9b01659.
- 1. State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing 210009 , China.
- 2. Department of Medicinal Chemistry, School of Pharmacy , China Pharmaceutical University , Nanjing 210009 , China.
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-5936), 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 (Kd = 0.5 μM) and cellular inhibitory activity (IC50 = 1.73 μM). 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.