Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors

Bioorg Chem. 2022 Apr:121:105669. doi: 10.1016/j.bioorg.2022.105669. Epub 2022 Feb 11.

Abstract

FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.

Keywords: AML; Antitumor; CDK4; Dual Inhibitor; FLT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase 4
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Protein Kinase Inhibitors
  • Pyridines
  • Structure-Activity Relationship
  • fms-Like Tyrosine Kinase 3

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • pyridine