Abstract
Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Azetidines / therapeutic use
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Crystallography, X-Ray
-
Dogs
-
Drug Combinations
-
Drug Synergism
-
Female
-
Humans
-
Madin Darby Canine Kidney Cells
-
Mice
-
Mice, Nude
-
Molecular Structure
-
Mutation
-
Neoplasms / drug therapy*
-
Phenylurea Compounds / chemistry
-
Phenylurea Compounds / metabolism
-
Phenylurea Compounds / therapeutic use*
-
Piperidines / therapeutic use
-
Protein Binding
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / metabolism
-
Protein Kinase Inhibitors / therapeutic use*
-
Quinazolinones / chemistry
-
Quinazolinones / metabolism
-
Quinazolinones / therapeutic use*
-
Structure-Activity Relationship
-
Xenograft Model Antitumor Assays
-
raf Kinases / antagonists & inhibitors*
-
raf Kinases / genetics
-
raf Kinases / metabolism
Substances
-
Azetidines
-
Drug Combinations
-
Phenylurea Compounds
-
Piperidines
-
Protein Kinase Inhibitors
-
Quinazolinones
-
raf Kinases
-
cobimetinib