Evolution of kinase polypharmacology across HSP90 drug discovery

Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.

Automated summary

This study identified and systematically characterized the kinase cross-pharmacology of representative HSP90 inhibitors using computational and experimental methods, revealing unique off-target kinase pharmacology of certain clinical candidates. It was also shown that polypharmacology evolved during optimization to discover luminespib, with hit, leads, and clinical candidate having different profiles. The study recommends early computational and experimental characterization of polypharmacology in drug discovery projects to uncover new opportunities for multi-target drug design.