Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds

J Med Chem. 2012 Apr 12;55(7):3452-78. doi: 10.1021/jm300126x. Epub 2012 Mar 14.

Abstract

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology
  • Benzoates / chemical synthesis
  • Benzoates / pharmacokinetics
  • Benzoates / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Phosphorylation
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Pyridazines / chemical synthesis
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • 2-chloro-3-(1-cyanocyclopropyl)-N-(5-((2-((cyclopropylcarbonyl)amino)(1,3)thiazolo(5,4-b)pyridin-5-yl)oxy)-2-fluorophenyl)benzamide
  • Antineoplastic Agents
  • Benzamides
  • Benzoates
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imidazoles
  • Pyridazines
  • Thiazoles
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3

Associated data

  • PDB/3VNT
  • PDB/4DBN