Discovery of novel indirubin-3'-monoxime derivatives as potent inhibitors against CDK2 and CDK9

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2447-51. doi: 10.1016/j.bmcl.2015.03.066. Epub 2015 Mar 31.

Abstract

Indirubin-3'-monoxime (IM) is a potent cyclin-dependent kinase (CDK) inhibitor. Twenty novel IM derivatives were prepared to investigate the structure-activity relationships (SAR) of this compound class. Six compounds showed significant inhibition against both CDK2/cyclin E1 and CDK9/cyclin T1. The most potent compound 7t exhibited IC50 values at submicromolar level. Preliminary SAR trends were suggested and cytotoxicity of these compounds was investigated. Molecular docking studies on compounds 7l and 7t provided conducive clues for further structural optimization.

Keywords: Cyclin-dependent kinase 2; Cyclin-dependent kinase 9; Indirubin-3′-oxime derivatives; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2 / adverse effects*
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Drug Discovery
  • Humans
  • Indoles / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Oximes / chemistry*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Indoles
  • Oximes
  • indirubin-3'-monoxime
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 9