Discovery of Dabrafenib: A Selective Inhibitor of
Raf Kinases with Antitumor Activity against B‑Raf-Driven Tumors
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Abstract
Hyperactive signaling of the MAP
kinase pathway resulting from
the constitutively active B-Raf<sup>V600E</sup> mutated enzyme has
been observed in a number of human tumors, including melanomas. Herein
we report the discovery and biological evaluation of GSK2118436, a
selective inhibitor of Raf kinases with potent in vitro activity in
oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and
robust in vivo antitumor and pharmacodynamic activity in mouse models
of B-Raf<sup>V600E</sup> human melanoma. GSK2118436 was identified
as a development candidate, and early clinical results have shown
significant activity in patients with B-Raf mutant melanoma