Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors

J Med Chem. 2014 May 22;57(10):3939-65. doi: 10.1021/jm401742r. Epub 2014 May 2.

Abstract

Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate, and phosphinate moieties were synthesized. Prepared compounds were evaluated in an enzymatic CDK9/CycT1 assay. The most potent molecules were tested in cell-based toxicity and HIV proliferation assays. Selectivity of shortlisted compounds against CDKs and other kinases was tested. The best compound was shown to be a highly specific, ATP-competitive inhibitor of CDK9/CycT1 with antiviral activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • Cyclin T / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Humans
  • Phosphorus
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • CCNT1 protein, human
  • Cyclin T
  • Protein Kinase Inhibitors
  • Phosphorus
  • Cyclin-Dependent Kinase 9