Discovery of a novel covalent CDK4/6 inhibitor based on palbociclib scaffold

Eur J Med Chem. 2021 Jul 5:219:113432. doi: 10.1016/j.ejmech.2021.113432. Epub 2021 Apr 3.

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.

Keywords: CDK4; CDK6; Cell cycle; Covalent inhibitor; Palbociclib.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Binding Sites
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Drug Design*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Piperazines / chemistry*
  • Piperazines / metabolism
  • Piperazines / therapeutic use
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyridines / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib