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

Seung Hye Choi, Injae Shin, Namdoo Kim, Yunju Nam, Taebo Sim

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)315-320
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume532
Issue number2
DOIs
Publication statusPublished - 2020 Nov 5

Bibliographical note

Funding Information:
Funding: This work was supported by a grant (2E29260) from Korea Institute of Science and Technology (KIST) , and the KU-KIST Graduate School of Converging Science and Technology Program . This research was also supported by the Candidate Development Program ( NRF2016M3A9B5940991 ) from the National Research Foundation in Korea .

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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