Discovery of a Stable Macrocyclic O-Aminobenzamide Hsp90 Inhibitor Which Significantly Decreases Tumor Volume in a Mouse Xenograft Model

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4602-7. doi: 10.1016/j.bmcl.2011.05.102. Epub 2011 Jun 27.

Abstract

An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use
  • Binding Sites
  • Biomarkers / metabolism
  • Drug Evaluation, Preclinical
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Macrocyclic Compounds / chemistry*
  • Mice
  • Mice, Nude
  • Microsomes, Liver / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Benzamides
  • Biomarkers
  • HSP90 Heat-Shock Proteins
  • Macrocyclic Compounds
  • benzamide