Identification of type II inhibitors targeting BRAF using privileged pharmacophores

Chem Biol Drug Des. 2014 Jan;83(1):27-36. doi: 10.1111/cbdd.12198. Epub 2013 Oct 25.

Abstract

V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4-phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non-small-cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG-out conformation of BRAF.

Keywords: drug design; kinase; pharmacophore; type II inhibitor; urea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Mutation
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemical synthesis
  • Urea / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-methyl-6-morpholinopyrimidin-4-ylamino)phenyl)urea
  • Antineoplastic Agents
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Urea
  • Proto-Oncogene Proteins B-raf
  • pyrimidine