Evolution of kinase polypharmacology across HSP90 drug discovery

摘要: 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 systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that resorcinol clinical candidates ganetespib and, a lesser extent, luminespib, display unique off-target pharmacology as compared other also evolved optimisation discover luminespib hit, leads candidate all have different polypharmacological profiles. conclude submicromolar inhibition protein kinases by may potential significance recommend characterization earlier in discovery projects unlock new multi-target design opportunities.