Dabrafenib

Dabrafenib (GSK2118436A) is an ATP-competitive inhibitor of Raf with IC₅₀s of 5 nM and 0.6 nM for C-Raf and B-Raf^V600E, respectively^[4]. IC50 & Target: IC50: 0.6 nM (BRAF^V600E), 5 nM (CRAF)^[4] In Vitro: Dabrafenib (GSK2118436, 1 μM) with 0.01 μM GSK1120212 inhibits more than 90% of cell growth in the NRAS mutant clones. GSK2118436 is sufficient to reduce S6P phosphorylation in A375^[1]. Dabrafenib suppresses the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6^[2]. Dabrafenib inhibits the release of HMGB1 and downregulates HMGB1-dependent inflammatory responses by enhancing the expressions of cell adhesion molecules (CAMs) in human endothelial cells^[3]. In Vivo: Dabrafenib-treated females have mostly immature reproductive tracts with no evidence of ovulation, similar to age-matched controls; however, DAB-treated females have keratinized and histologically open vaginas^[5].