Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127040. doi: 10.1016/j.bmcl.2020.127040. Epub 2020 Feb 17.

Abstract

Kinases are signalling proteins which have proven to be successful targets for the treatment of a variety of diseases, predominantly in cancers. However, only a small proportion of kinases (<20%) have been investigated for their therapeutic viability, likely due to the lack of available chemical tools across the kinome. In this work we describe initial efforts in the development of a selective chemical tool for protein kinase N2 (PKN2), a relatively unexplored kinase of interest in several types of cancer. The most successful compound, 5, has a measured IC50 of 0.064 μM against PKN2, with ca. 17-fold selectivity over close homologue, PKN1.

Keywords: AGC kinase; Benzimidazole; Cancer; Chemical probe; Chemical tool; Heart failure; Inflammation; Kinases; PKN2; PRK2; Protein kinase N2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Development*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • protein kinase N
  • Protein Kinase C