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CEP-32496 is a highly potent and orally efficacious V600E mutant BRAF, WT BRAF and c-Raf inhibitor with Kd values of 14 nM, 36 nM and 39 nM, respectively.

In addition to BRAFV600E, CEP-32496 has exhibited high binding affinity for both wild-type BRAF and related CRAF, as well as certain receptor tyrosine kinases of known therapeutic utility, such as Abl-1, c-Kit, Ret, PDGFR-β, and VEGFR-2. However, CEP-32496 proved selective for the RAF members of the MAPK signal transduction pathway, as no significant affinity was observed for other key kinases of the MAPK pathway, including MEK-1, MEK-2, ERK-1, and ERK-2. This suggests that the observed cellular activity was driven primarily through inhibition of BRAFV600E, which is further supported by the observation that CEP-32496 exhibited selective cytotoxicity for tumor cell lines expressing mutant BRAF versus those expressing wild-type BRAF [1].

Oral administration of CEP-32496 to Colo-205 tumor xenograft-bearing mice resulted in significant inhibition of pMEK in tumor cell lysates [1].

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