产品描述:
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-RAFV600E, and wild-type C-RAF kinase, respectively).{42963} 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-RAFV600E (GI50s = 50s = 50s = 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-RAFV600E-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-RAFV600E-expressing cancers.