Dabrafenib (mesylate)

Dabrafenib is an ATP-competitive inhibitor of Raf kinases (IC₅₀s = 0.64, 0.68, and 5 nM for wild-type B-RAF kinase, mutant B-RAF^V600E, and wild-type C-RAF kinase, respectively).¹ It also inhibits the tyrosine kinase-like kinases ALK5 and LIMK1 (IC₅₀s = 11 and 15 nM, respectively) and the calcium/calmodulin-dependent protein kinases SIK2 and PDK2 (IC50s = 27 and 57 nM, respectively), as well as NEK11, CK1, and BRK (IC₅₀s = 20, 41, and 79 nM, respectively) in a panel of 270 kinases at 300 nM. Dabrafenib inhibits the growth of 16 cancer cell lines expressing mutant B-RAF^V600E (GI50s = <200 nM), five cell lines expressing other B-RAF mutants (GI₅₀s = <30 nM), and 19 cell lines expressing wild-type Ras and RAF (GI₅₀s = <7,000 nM). However, it does not inhibit the growth of four cancer cell lines expressing mutant B-RAF^V600E, 133 cell lines expressing wild-type Ras and Raf, or 18 cell lines expressing mutant Ras (GI₅₀s = >10 µM) in a panel of 195 cancer cell lines. Dabrafenib (8 nM) inhibits MAPK signaling, inhibiting phosphorylation of MEK and ERK, and activates caspase-3/7 in B-RAF^V600E-expressing A375P melanoma cells but not in wild-type B-RAF-expressing human foreskin fibroblasts (EC₂₀₀s =71 and >10,000 nM, respectively). It reduces tumor growth in an A375P mouse xenograft model when administered at doses ranging from 3 to 100 mg/kg. Formulations containing dabrafenib have been used in the treatment of B-RAF^V600E-expressing cancers.

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1. King, A.J., Arnone, M.R., Bleam, M.R., et al. Dabrafenib; Preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One 8(7), e67583 (2013).