Discovery and SARs of 5-Chloro- N4-phenyl- N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity

J Med Chem. 2020 Mar 26;63(6):3327-3347. doi: 10.1021/acs.jmedchem.9b02121. Epub 2020 Mar 12.

Abstract

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / chemistry
  • Cyclin-Dependent Kinase 6 / metabolism
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / chemistry
  • Cyclin-Dependent Kinase 9 / metabolism
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Protein Binding
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridines / administration & dosage
  • Pyridines / chemical synthesis
  • Pyridines / metabolism
  • Pyridines / therapeutic use*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis
  • Pyrimidines / metabolism
  • Pyrimidines / therapeutic use*
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase 9