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

Bioorg Med Chem. 2014 Jan 15;22(2):892-905. doi: 10.1016/j.bmc.2013.11.036. Epub 2013 Nov 25.

Abstract

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=0.52nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50=0.098μM, NCI-N87 IC50=0.066μM) 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%).

Keywords: Antitumor agent; Hsp90 inhibitor; Lead optimization; Structure-based drug design.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzopyrans / administration & dosage
  • Benzopyrans / chemical synthesis
  • Benzopyrans / pharmacology*
  • Biological Availability
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • HCT116 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Structure-Activity Relationship
  • Triazines / administration & dosage
  • Triazines / chemical synthesis
  • Triazines / pharmacology*

Substances

  • Benzopyrans
  • HSP90 Heat-Shock Proteins
  • Triazines