CCT239065 is a novel, selective, and efficacious nanomolar pyridopyrazinone V600EBRAF and LCK inhibitor with IC50 of 13 and 6 nM, respectively. CCT239065 is active against oncogenic BRAF in cells. CCT239065 also inhibits BRAF, CRAF and SRC with IC50 of 81, 12 and 23 nM, respectively. CCT239065 is more than 6-fold less active against wild-type BRAF and more than 50-fold less active against EGFR2/KDR than against V600EBRAF. CCT239065 inhibits ERK1/2 phosphorylation at 5 nM in WM266.4 cells. CCT239065 achieves high levels of selectivity in vitro and at 1 μM, a concentration that is approximately 50 times higher than its IC50 value against purified V600EBRAF. CCT239065 reveals a very low plasma clearance (0.4 mL/hour) consistent with the absence of metabolism and a terminal half-life of 6.8 hours.Plasma concentrations of CCT239065 achieve over 100-fold greater than the average GI50 value for BRAF mutant cancer cell lines in vitro and are sustained above the average GI50 in plasma and muscle (used as a tumor tissue surrogate) for over 18 hours. CCT239065 is well tolerated in mice and displays excellent oral bioavailability. Inhibition of V600EBRAF-mediated signaling in human tumor xenografts is observed following oral administration of a single dose of CCT239065.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
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