关键词： Anti-proliferation activity HSP90-CDC37 Kinase maturation Protein-protein interaction inhibitors

Mesh ： Animals Antineoplastic Agents / chemistry pharmacology Cell Cycle Proteins / metabolism Cell Proliferation / drug effects Chaperonins / metabolism Drug Design HCT116 Cells HSP90 Heat-Shock Proteins / metabolism Humans Hydrophobic and Hydrophilic Interactions / drug effects Mice Models, Molecular Neoplasms / drug therapy metabolism Protein Interaction Maps / drug effects

来  源：   DOI：10.1016/j.ejmech.2020.112959   PDF(Sci-hub)

Abstract：
HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (KD = 5.52 μM) and antiproliferative activity (IC50 = 6.34 μM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.
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