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.
Highlights
Melanoma is a highly aggressive type of skin cancer with its worldwide incidence increasing over the recent 50 years [1,2,3]
Metastatic melanoma is highly linked with poor prognosis and is considered a very aggressive, lethal form of cancer
We report that SIJ1777, a novel GNF-7 derivative, possesses potent anti-cancer effects on melanoma cells harboring BRAF class I/II/III mutations
Summary
Melanoma is a highly aggressive type of skin cancer with its worldwide incidence increasing over the recent 50 years [1,2,3]. To overcome drug resistance of vemurafenib, PLX8394 has been developed as a generation RAF inhibitor that does not induce paradoxical ERK activation This paradox breaker possesses limited effects against class II and class III BRAF mutants [9]. On the basis of our analysis, we, anticipate that it is worth carrying out further exploration of novel pan-class BRAF inhibitors and performing further research focused on melanoma in order to override vemurafenib-resistance. To this end, we describe the identification of novel kinase inhibitors possessing potent inhibitory activities against melanoma cells harboring class II (G464E) and class III (G469E, D594G) as well as class I (V600E) BRAF mutations
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