Agerafenib

• CAT Number: I009240
• CAS Number: 1188910-76-0
• Molecular Formula: C24H22F3N5O5
• Molecular Weight: 517.46
• Purity: ≥95%
• Synonyms: 1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea
• InChI: InChI=1S/C24H22F3N5O5/c1-23(2,24(25,26)27)19-11-20(32-37-19)31-22(33)30-13-6-5-7-14(8-13)36-21-15-9-17(34-3)18(35-4)10-16(15)28-12-29-21/h5-12H,1-4H3,(H2,30,31,32,33)
• InChIKey: DKNUPRMJNUQNHR-UHFFFAOYSA-N
• SMILES: CC(C)(C1=CC(=NO1)NC(=O)NC2=CC(=CC=C2)OC3=NC=NC4=CC(=C(C=C43)OC)OC)C(F)(F)F

Agerafenib (CEP-32496; RXDX-105) is a highly potent and orally efficacious inhibitor of BRAFV600E with a Kd of 14 nM.
Agerafenib (CEP-32496) exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. Agerafenib exhibits potent binding (BRAFV600E 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[1].
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].

Reference

[1]. Rowbottom MW, et al. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E.
 [Content Brief]