Agerafenib hydrochloride, a highly potent inhibitor of BRAFV600E (Kd: 14 nM), demonstrates significant efficacy.

EGFR:22 nM （kd）, B-Raf (V600E):14 nM （kd）, BRAF:36 nM （kd）, c-Kit:2 nM （kd）, JAK2:4700 nM （kd）, Raf:39 nM （kd）, VEGFR2:8 nM （kd）, MEK2:8300 nM （kd）, MEK1:7100 nM （kd）, Abl-1:3 nM （kd）, CSF1R:9 nM （kd）, EphA2:14 nM （kd）, Lck:2 nM （kd）, RET:2 nM （kd）, c-Met:513 nM （kd）

Agerafenib exhibits high potency against several BRAF V600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF V600E. It shows potent binding (BRAF V600E, Kd: 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.

Agerafenib exhibits an exceptional PK profile in mouse, dog, and cynomolgus monkey. Administration of Agerafenib to beagle dogs (single dose of 1 mg/kg i.v and 10 mg/kg p.o) 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 i.v and 10 mg/kg p.o) leads to high oral exposure due to low clearance (CL=6.7 mL/min/kg) and excellent bioavailability (%F=100). Oral administration of Agerafenib to Colo-205 tumor xenograft-bearing mice results in significant inhibition of pMEK in tumor cell lysates.