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.
| Molecular Weight | 555.65 |
| Formula | C29H29N7O3S |
| CAS Number | 1163719-51-4 |
| Solubility (25°C) | DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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