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.

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S1069 Luminespib (NVP-AUY922) Luminespib (AUY-922, NVP-AUY922, VER-52296) is a highly potent HSP90 inhibitor for HSP90α/β with IC50 of 13 nM /21 nM in cell-free assays, weaker potency against the HSP90 family members GRP94 and TRAP-1, exhibits the tightest binding of any small-molecule HSP90 ligand. Luminespib (AUY-922, NVP-AUY922) effectively downregulates and destabilizes the IGF-1Rβ protein and results in growth inhibition, autophagy and apoptosis. Phase 2. (93) (3)

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