Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening

• A novel Hsp90 inhibitor 36 with the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine core was identified by ROCS.
• Eight 36 derivatives were designed and synthesized by structure-based method.
• The derivative 57h exhibited improvement potency both in target-based and cell-based level.

Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a–57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.

Shape-based similarity screening, structure-based design and synthesis were performed to discover Hsp90 inhibitors.Figure optionsDownload as PowerPoint slide