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

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.