tcsc1115 Agerafenib (CEP-32496;RXDX105)

Agerafenib (CEP-32496; RXDX-105) is a highly potent and orally efficacious inhibitor of BRAF^V600E with a K_d of 14 nM.

IC50 & Target: Kd: 14 nM (BRAF^V600E), 36 nM (wt BRAF),39 nM (CRAF), 2 nM (c-Kit), 2 nM (Ret), 2 nM (LCK), 3 nM (Abl-1), 8 nM (VEGFR-2), 9 nM (CSF-1R), 14 nM (EPHA2), 22 nM (EGFR), 513 nM (c-Met), 4700 nM (JAK-2), 7100 nM (MEK-1), 8300 nM (MEK-2)^[1]

In Vitro: Agerafenib (CEP-32496) exhibits high potency against several BRAF^V600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF^V600E versus those containing wild-type BRAF. Agerafenib exhibits potent binding (BRAF^V600E K_d=14 nM) and cellular activity (pMEK IC₅₀=82 nM and A375 proliferation IC₅₀=78 nM), with activity in the proliferation assay. Agerafenib also exhibits a favorable CYP450 inhibition profile, with measured IC₅₀ values greater than 10 μM versus the CYP1A2, CYP2C9, CYP2D6, and CYP3A4 isoforms and an IC₅₀=3.4 μM versus CYP2C19^[1].

In Vivo: Oral administration of Agerafenib (CEP-32496) to Colo-205 tumor xenograft-bearing mice results in significant inhibition of pMEK in tumor cell lysates. For instance, a single 30 mg/kg (po) dose of Agerafenib leads to a 50 and 75% inhibition of normalized pMEK in tumor lysates at the 2 and 6 h postdose time point, respectively (p<0.03), while a 55 mg/kg (po) dose resulted in a 75% to 57% (p<0.03) inhibition of pMEK at 2 through 10 h post administration, with normalization to baseline by 24 h. Agerafenib exhibits an exceptional PK profile in mouse, dog, and cynomolgus monkey. Administration of Agerafenib to beagle dogs (single dose of 1 mg/kg iv and 10 mg/kg po) results in low clearance (CL=5.0 (mL/min)/kg) and excellent bioavailability (%F=100). Similarly, in cynomolgus monkey, the administration of Agerafenib (single dose of 1 mg/kg iv and 10 mg/kg po) leads to high oral exposure due to low clearance (CL=6.7 mL/min/kg) and excellent bioavailability (%F=100)^[1].