The first small molecules capable of strongly suppressing proliferation of cancer cells harboring BRAF class I/II/III mutations.

Abstract

BRAF mutants are categorized into three classes according to dependency on RAS signaling and RAF dimerization-dependency. Class I BRAF V600 mutants (RAS-independent monomer) are sensitive to vemurafenib. In contrast, both class II mutants (RAS-independent dimer) and class III mutants (RAS-dependent heterodimer) are insensitive to vemurafenib. It is not likely that BRAF inhibitors capable of inhibiting all classes of BRAF mutants are currently available. Herein, we report GNF-7 and its novel derivative, SIJ1227 as the first BRAF inhibitors capable of inhibiting all classes of BRAF mutants. Compared with vemurafenib and PLX8394, both GNF-7 and SIJ1227 possess much more strong anti-proliferative activities on melanoma (A375 and C8161) and lung cancer cells (H1755 and H1666) harboring BRAF V600E (class I mutant), BRAF G464E/G469A (class II mutant) and BRAF G466V (class III mutant), respectively. Also, both GNF-7 and SIJ1227 are capable of inhibiting more strongly colony formation than vemurafenib and PLX8394 in 3D soft agar assay using C8161 melanoma cells. In addition, GNF-7 and SIJ1227 suppress more strongly migration/invasion of these cancer cells than vemurafenib and PLX8394. Taken together, both GNF-7 and SIJ1227 are much superior to vemurafenib and PLX8394 in terms of capability to inhibit all classes of BRAF mutants.

• Authors: Seung-Hye Choi, Injae Shin, Namdoo Kim, Yunju Nam, Taebo Sim
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 532 Issue 2 Pg. 315-320 (11 05 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32873393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• N-(4-methyl-3-(1-methyl-7-(6-methylpyridin-3-ylamino)-2-oxo-1,2-dihydropyrimido(4,5-d)pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide
• Protein Kinase Inhibitors
• Pyrimidinones
• Vemurafenib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor (methods)
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Melanoma (drug therapy, genetics, pathology)
• Molecular Docking Simulation
• Mutation
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, chemistry, genetics)
• Pyrimidinones (pharmacology)
• Vemurafenib (pharmacology)