The design and synthesis of a new class of RTK/HDAC dual-targeted inhibitors

Molecules. 2013 Jun 3;18(6):6491-503. doi: 10.3390/molecules18066491.

Abstract

Over the years, the development of targeted medicines has made significant achievements. As a typical example, receptor tyrosine kinases (RTK) inhibitors have become important chemotherapy drugs for a variety of cancers. However, the effectiveness of these agents is always hindered by poor response rates and acquired drug resistance. In order to overcome these limitations, several dual-targeted inhibitors with quinazoline core were designed and synthesized. Though these compounds can simultaneously inhibit histone deacetylases (HDAC) as well as RTK, the structure-activity relationship (SAR) is still not clear enough. To further explore this type of dual-targeted inhibitors, a new class of quinazoline derivatives were designed and synthesized. Their activity evaluations include in vitro inhibitory activity of HDAC, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The SAR study indicated that the introduction of polar group such as hydroxamate on the 4-position of the quinazoline core is more likely to provide a potent HDACi/HER2i hybrid rather than HDACi/EGFRi molecule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • ErbB Receptors / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor, ErbB-2 / antagonists & inhibitors

Substances

  • Histone Deacetylase Inhibitors
  • Protein Kinase Inhibitors
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2