Discovery of wrightiadione as a novel template for the TrkA kinase inhibitors

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5186-9. doi: 10.1016/j.bmcl.2015.09.070. Epub 2015 Sep 30.

Abstract

Enzymatic kinase assays and docking simulation studies have shown that the natural product wrightiadione displays inhibitory activity toward TrkA and PLK3. In this study, the template of wrightiadione served as a starting point for Trk inhibitor development campaigns. Molecular simulation provided structural insights for the design of derivatives that were efficiently generated by our recently developed 3-step tandem synthetic approach, resulting in the discovery of compound 2h with biochemical potency at the single-digit micromolar level.

Keywords: Anticancer; Kinase; Modeling; Trk inhibitor; Wrightiadione.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry*
  • Humans
  • Indenes / chemistry*
  • Isoflavones / chemistry*
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Quinolines / chemistry*
  • Receptor, trkA / antagonists & inhibitors*
  • Receptor, trkA / chemistry

Substances

  • 8-methoxy-5-methyl-5H-indeno(2,1-b(quinoline-6,11-dione
  • Antineoplastic Agents, Phytogenic
  • Indenes
  • Isoflavones
  • Protein Kinase Inhibitors
  • Quinolines
  • wrightiadione
  • Receptor, trkA