Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group

J Med Chem. 2018 Nov 21;61(22):10242-10254. doi: 10.1021/acs.jmedchem.8b01229. Epub 2018 Nov 5.

Abstract

Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro. The potency and selectivity of 19 for MERTK over FLT3 were confirmed in cell-based assays using human cancer cell lines. Compound 19 had favorable pharmacokinetic properties in mice. Phosphorylation of MERTK was decreased by 75% in bone marrow leukemia cells from mice treated with 19 compared to vehicle-treated mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Methylation
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Tissue Distribution
  • c-Mer Tyrosine Kinase / antagonists & inhibitors*
  • c-Mer Tyrosine Kinase / chemistry
  • c-Mer Tyrosine Kinase / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • c-Mer Tyrosine Kinase