1. Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
- Author
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Eunhye Ju, Injae Shin, Eunhye Jeon, SeongShick Ryu, Wonjeong Cho, Namkyoung Kim, Ji Won Lee, Taebo Sim, and Young Hoon Kim
- Subjects
Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Mutant ,Antineoplastic Agents ,Drug resistance ,vemurafenib-resistant ,Catalysis ,Article ,lcsh:Chemistry ,Inorganic Chemistry ,Cell Line, Tumor ,medicine ,melanoma ,Humans ,Physical and Theoretical Chemistry ,Vemurafenib ,type-II kinase inhibitor ,lcsh:QH301-705.5 ,Molecular Biology ,Protein kinase B ,neoplasms ,Spectroscopy ,Chemistry ,Melanoma ,Organic Chemistry ,General Medicine ,medicine.disease ,pan-class BRAF inhibitor ,Computer Science Applications ,BRAF class I/II/III mutants ,lcsh:Biology (General) ,lcsh:QD1-999 ,Drug Resistance, Neoplasm ,Apoptosis ,Mutation ,Cancer research ,Skin cancer ,medicine.drug - 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.
- Published
- 2021