Recent Advances in the Design and Synthesis of c-Met Inhibitors as Anticancer Agents (2014-Present)

Curr Med Chem. 2017;24(1):57-64. doi: 10.2174/0929867323666161028161441.

Abstract

c-Met, also known as the surface receptor of hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with heterodimer transmembrane. c-Met involves in the activation of several signaling pathways, most of them are implicated in aggressive cancer phenotypes. In a variety of human malignances, c-Met/HGF signaling has been found aberrant, and in many instances, has been correlated with advanced disease stage and poor prognosis. Thus, the c-Met has identified as an emerging and interesting target for cancer chemotherapy. In this review, we briefly summarize signaling pathways of c-Met, and discuss the crystal structures of representative c-Met and the binding modes with their ligands. We also present updates on the design, synthesis and structure-activity relationship analysis of c-Met inhibitors developed from 2014 till now. At last, we review the c-Met inhibitors that are in clinical development and highlight the future prospects.

Keywords: ATP-competitive inhibitors; anticancer agents; binding modes; c-Met inhibitors; hepatocyte growth factor receptor (HGFR); structure-activity relationship analysis.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism

Substances

  • Antineoplastic Agents
  • Ligands
  • Protein Kinase Inhibitors
  • MET protein, human
  • Proto-Oncogene Proteins c-met