Selective degradation of CDK6 by a palbociclib based PROTAC

Bioorg Med Chem Lett. 2019 Jun 1;29(11):1375-1379. doi: 10.1016/j.bmcl.2019.03.035. Epub 2019 Mar 26.


Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.

Keywords: CDK6; CDK6 degrader; PROTAC; Palbociclib.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteolysis / drug effects*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship


  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • palbociclib