Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance.

Abstract

Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF V600 mutations are sensitive to vemurafenib whereas class II and class III mutants, non-V600 BRAF mutants are resistant to vemurafenib. Herein we report six pyrimido[4,5-d]pyrimidin-2-one derivatives possessing highly potent anti-proliferative activities on melanoma cells harboring BRAF class I/II/III mutants. Novel and most potent derivative, SIJ1777, possesses not only two-digit nanomolar potency but also 2 to 14-fold enhanced anti-proliferative activities compared with reference compound, GNF-7 against melanoma cells (SK-MEL-2, SK-MEL-28, A375, WM3670, WM3629). Moreover, SIJ1777 substantially inhibits the activation of MEK, ERK, and AKT and remarkably induces apoptosis and significantly blocks migration, invasion, and anchorage-independent growth of melanoma cells harboring BRAF class I/II/II mutations while both vemurafenib and PLX8394 have little to no effects on melanoma cells expressing BRAF class II/III mutations. Taken together, our six GNF-7 derivatives exhibit highly potent activities against melanoma cells harboring class I/II/III BRAF mutations compared with vemurafenib as well as PLX8394.

• Authors: Namkyoung Kim, Injae Shin, Jiwon Lee, Eunhye Jeon, Younghoon Kim, Seongshick Ryu, Eunhye Ju, Wonjeong Cho, Taebo Sim
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 7 (Apr 06 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33917428 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Melanoma (drug therapy, genetics, metabolism, pathology)
• Mutation
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)