Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate

Bioorg Med Chem Lett. 2017 Feb 15;27(4):1099-1104. doi: 10.1016/j.bmcl.2016.12.024. Epub 2016 Dec 20.

Abstract

Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.

Keywords: Axl; Crystallography; Mer; Modeling; Oncology design; SBDD; Structure design.

MeSH terms

  • Axl Receptor Tyrosine Kinase
  • Crystallography, X-Ray
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Molecular Structure
  • Mutation*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • c-Mer Tyrosine Kinase

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase
  • Axl Receptor Tyrosine Kinase