CEP-32496

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

CEP-32496 是 BRAF(V600E/WT) 和 c-Raf 的高效抑制剂，Kd 为 14 nM/36 nM 和 39 nM。

CEP-32496 is a highly potent inhibitor of BRAF(V600E/WT) and c-Raf with Kd of 14 nM/36 nM and 39 nM, also potent to Abl-1, c-Kit, Ret, PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. Phase 1/2.(In Vitro):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 versus CYP2C19. (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).

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Tyrosine Kinase

Bcr-Abl

Abl1| c-Kit| RET| PDGFRβ| Lck

Cancer

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1188910-76-0

517.46

C24H22F3N5O5

>98% (HPLC)

DMSO: 9 mg/mL (17.39 mM)

COC1=C(OC)C=C2C(OC3=CC=CC(NC(=O)NC4=NOC(=C4)C(C)(C)C(F)(F)F)=C3)=NC=NC2=C1

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(-20℃)

With Ice Pack

≥ 2 years