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CEP-32496 is a selective inhibitor of BRAFV600E with IC50 value of 669 nM [1].

BRAF is a member of Raf kinase family and plays an important role in sending signals (directing cell growth) inside cells. BRAF involves in regulating MAP kinase/ERKs signaling pathway and mutant BRAFV600E activates MAPK pathway, it has been shown that BRAF mutant BRAFV600E is correlated with several human cancers [2].

CEP-32496 is a potent BRAFV600E inhibitor and has a different selectivity with the reported BRAFV600E inhibitor RG7204. Using Ambit Kinomescan Assay, it was shown that CEP-32496 potently binding to RAF family with Kd value ranged from 14 to 39 nmol/L. When tested with a panel of BRAF mutant (A375, SK-MEL-28, Colo-679, HT-144, and Colon-205) cell lines, CEP-32496 showed a selective cytotoxicity profile against tumor cell lines with V600E mutant while had no effect on wild type cell lines (HCT116, Hs578T, LNCaP, DU145, PC-3) [1]. CEP-32496 treatment exhibited high cytotoxicity against human tumor cell lines with expression of BRAFV600E while had little effect on wild type BRAF expressed cell lines [2].

In nude mice model with Colo-205 tumor cells subcutaneous xenograft, oral administration of CEP-32496 significantly inhibited pMEK normalization, induced tumor stasis (40%) while control group did not have this phenomenon in a dose of 30 mg/kg [1].

CEP-32496 also inhibits MEK phosphorylation with IC 50 value of 60 nM [1].

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