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

Eur J Med Chem. 2014 May 22:79:399-412. doi: 10.1016/j.ejmech.2014.03.061. Epub 2014 Mar 21.

Abstract

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.

Keywords: Design and synthesis; Hsp90 inhibitors; ROCS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • HCT116 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Pyrimidines