Synthesis of triazolotriazine derivatives as c-Met inhibitors

Mol Divers. 2021 May;25(2):839-846. doi: 10.1007/s11030-020-10067-5. Epub 2020 Mar 10.

Abstract

Receptor tyrosine kinase c-Met is an important antitumor drug target. Triazolotriazine analogues 2-10 were prepared efficiently and evaluated the enzymatic and cellular c-Met activities. Brief structure-activity relationships of triazolotriazine core and CF2-quinoline part were investigated, leading to the discovery of compound 8 with nanomolar enzymatic c-Met activity, and subnanomolar MKN45 and EBC-1 cellular potencies. The proposed binding model of 8 and c-Met unraveled that two canonical hydrogen bonds and a π-π stacking interaction formed between the inhibitor and the ATP binding site of c-Met kinase domain, which accounted for its potent c-Met activities.

Keywords: Cellular potency; Receptor tyrosine kinase; SAR; Triazolotriazine; c-Met.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Quinolines* / chemical synthesis
  • Quinolines* / chemistry
  • Quinolines* / pharmacology
  • Structure-Activity Relationship
  • Triazines* / chemical synthesis
  • Triazines* / chemistry
  • Triazines* / pharmacology

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinolines
  • Triazines
  • Proto-Oncogene Proteins c-met