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

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.

BRAF class I/II/III mutants; melanoma; pan-class BRAF inhibitor; type-II kinase inhibitor; vemurafenib-resistant.