Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy

Eur J Med Chem. 2018 Mar 25:148:140-153. doi: 10.1016/j.ejmech.2018.02.022. Epub 2018 Feb 12.

Abstract

CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth. The compound demonstrated favorable in vitro metabolic and robust mice pharmacokinetic properties. In Colo-205 xenograft models, compound 28 showed potent tumor growth inhibition with acceptable toxic effects, which could serve as a novel anticancer agent for further preclinical study.

Keywords: In vivo antitumor activity; Selective CDK4/6 inhibitors; Structure-activity relationship study; Structure-based drug design.

MeSH terms

  • Animals
  • Biological Availability
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Drug Design
  • Heterografts
  • Humans
  • Mice
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Tetrahydronaphthalenes / chemical synthesis*
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Tetrahydronaphthalenes
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases