1. The first small molecules capable of strongly suppressing proliferation of cancer cells harboring BRAF class I/II/III mutations
- Author
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Namdoo Kim, Taebo Sim, Yunju Nam, Injae Shin, and Seung Hye Choi
- Subjects
Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Lung Neoplasms ,endocrine system diseases ,Mutant ,Biophysics ,Antineoplastic Agents ,Apoptosis ,Pyrimidinones ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Lung cancer ,Vemurafenib ,Melanoma ,Protein Kinase Inhibitors ,neoplasms ,Molecular Biology ,Cell Proliferation ,Chemistry ,Cell Biology ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Small molecule ,digestive system diseases ,Molecular Docking Simulation ,BRAF V600E ,030104 developmental biology ,Colony formation ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,Cancer cell ,Cancer research ,Drug Screening Assays, Antitumor ,medicine.drug - 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.
- Published
- 2020