生物活性

• 靶点

  B-Raf (V600E) Kd:14nM

  B-Raf Kd:36nM

  C-Raf Kd:39nM

• 描述The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. The RAF members of this pathway consist of the serine/threonine kinases ARAF, BRAF, and CRAF, which phosphorylate and activate downstream MEK1/2. Expression of mutant BRAF^V600E results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. CEP-32496 is a highly potent and orally efficacious inhibitor of BRAF^V600E. It exhibits potent binding (BRAF^V600E K_d = 14 nM) and cellular activity (pMEK IC₅₀ = 82 nM and A375 proliferation IC₅₀ = 78 nM). Administration of CEP-32496 to beagle dogs (single dose of 1 mg/kg iv and 10 mg/kg po) resulted in low clearance (CL = 5.0 (mL/min)/kg) and excellent bioavailability (%F = 100). CEP-32496 also exhibited a favorable CYP450 inhibition profile, with measured IC₅₀ values greater than 10 μM versus the CYP1A2, 2C9, 2D6, and 3A4 isoforms and an IC₅₀ = 3.4 μM versus 2C19. Athymic nude mice bearing established Colo-205 tumor xenografts were dosed orally with CEP-32496 at 10, 30, and100 mg/kg twice daily (BID) over a 14-day period. All doses were well tolerated without mortality or significant body weight loss. The 30 mg/kg dose group exhibited tumor stasis and a 40% incidence of partial tumor regressions (PRs) (p < 0.008), whereas the 100 mg/kg BID dose group exhibited both tumor stasis and an 80% incidence of PRs (p < 0.0001). Oral administration of CEP-32496 to Colo-205 tumor xenograft-bearing mice resulted in significant inhibition of pMEK in tumor cell lysates. For instance, a single 30 mg/kg (po) dose of CEP-32496 led 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)^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01877811	Solid Tumors	Phase 1	Active, not recruiting	June 2019	United States, California ... more >> City of Hope Duarte, California, United States University of California Irvine College of Medicine Irvine, California, United States University of California San Diego Moores Cancer Center San Diego, California, United States United States, District of Columbia Lombardi Comprehensive Cancer Center, Georgetown Washington, District of Columbia, United States United States, Florida Florida Cancer Center Sarasota, Florida, United States United States, Georgia University Cancer & Blood Center, LLC Athens, Georgia, United States United States, Massachusetts Massachusetts General Hospital/Beth Israel Deaconess Med. Ctr./Dana Farber Cancer Institute Boston, Massachusetts, United States United States, Michigan Henry Ford Health System Detroit, Michigan, United States Karmanos Cancer Center Detroit, Michigan, United States United States, Missouri Washington University Saint Louis, Missouri, United States United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States United States, Pennsylvania Fox Chase Cancer Center Philadelphia, Pennsylvania, United States United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States United States, Washington University of Washington, Seattle Cancer Care Alliance Seattle, Washington, United States Collapse <<

• 参考文献

• [1] James J, Ruggeri B, et al. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity. Mol Cancer Ther. 2012 Apr;11(4):930-41.

  [2] Rowbottom MW, Faraoni R, et al. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropa n-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. J Med Chem. 2012 Feb 9;55(3):1082-105.

  [3] Rowbottom MW, Faraoni R, Chao Q, 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. J Med Chem. 2012;55(3):1082-1105.