Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors

A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90α (Kd = 0.52 nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50 = 0.098 μM, NCI-N87 IC50 = 0.066 μM) and also displayed high oral bioavailability in mice (F = 44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition = 136%).

A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as Hsp90 inhibitors were identified through structure-based drug design. Among them, CH5138303 showed high binding affinity for Hsp90, potent anti-proliferative activity, high oral bioavailability in mice and potent antitumor efficacy in a human cancer xenograft model.Figure optionsDownload as PowerPoint slide