Chromene-3-carboxamide Derivatives Discovered From Virtual Screening as Potent Inhibitors of the Tumour Maker, AKR1B10

Bioorg Med Chem. 2010 Apr 1;18(7):2485-90. doi: 10.1016/j.bmc.2010.02.050. Epub 2010 Mar 1.

Abstract

A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a therapeutic target in the treatment of several types of cancer. In order to identify potential leads for new inhibitors of AKR1B10, we adopted the virtual screening approach using the automated program icm, which resulted in the discovery of several chromene-3-carboxamide derivatives as potent competitive inhibitors. The most potent (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide inhibited the reductase activity of AKR1B10 with a K(i) value of 2.7nM, and the metabolism of farnesal and 4-hydroxynonenal in the AKR1B10-overexpressed cells from 0.1microM with an IC(50) value equal to 0.8microM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Aldehydes / metabolism
  • Aldo-Keto Reductases
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / pharmacology*
  • Biomarkers, Tumor / antagonists & inhibitors*
  • Catalytic Domain
  • Computer Simulation
  • Databases, Factual
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Farnesol / analogs & derivatives
  • Farnesol / metabolism
  • HeLa Cells
  • Humans
  • Kinetics
  • Models, Molecular
  • Protein Binding
  • Recombinant Proteins / chemistry
  • Substrate Specificity

Substances

  • Aldehydes
  • Antineoplastic Agents
  • Benzopyrans
  • Biomarkers, Tumor
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Farnesol
  • AKR1B10 protein, human
  • Aldo-Keto Reductases
  • Aldehyde Reductase
  • 4-hydroxy-2-nonenal
  • farnesal