Inhibition of V600E-B-RAF kinase represents a potential avenue for melanoma treatment. In this work, a novel series of 1,3,4-triarylpyrazoles possessing amide linker were designed, synthesized, and evaluated for RAF kinase inhibition. Compounds 1d and 1f were more potent than Sorafenib against A375 melanoma cell line, and their selectivity indexes towards A375 than HS27 fibroblasts were 25.43 and 45.83, respectively. Compound 1f was more potent against the melanoma cell lines with B-RAF V600E mutation than melanoma cells with NRAS mutation and normal skin epithelial cells. Compounds 1d and 1f showed strong potency and selectivity against V600E-B-RAF kinase with IC50 values of 3.80 nM and 2.98 nM, respectively. Molecular docking studies revealed their binding mode. As a result, potent and selective V600E-B-RAF anti-melanoma agents were discovered.

Design and synthesis of a novel series of highly potent RAF kinase-inhibiting triarylpyrazole derivatives with potential antiproliferative activity against melanoma

2019 Spring National Meeting

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