Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC)

Bioorg Med Chem Lett. 2014 Jan 1;24(1):224-7. doi: 10.1016/j.bmcl.2013.11.034. Epub 2013 Nov 22.

Abstract

Heat shock protein 90 (Hsp90) represents an attractive cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid Hsp90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure-based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of Hsp90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of Hsp70. The design, synthesis, and evaluation of 1f are described herein.

Keywords: Gefitinib resistance; Hsp90; Inhibitor; Lung cancer; Rational design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins