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Agerafenib

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Chemical Structure| 1188910-76-0 同义名 : RXDX-105;CEP-32496
CAS号 : 1188910-76-0
货号 : A144993
分子式 : C24H22F3N5O5
纯度 : 99%+
分子量 : 517.457
MDL号 : MFCD22124524
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(96.63 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

15% Captisol+water 15 mg/mL suspension

生物活性
靶点

  • B-Raf

    B-Raf, Kd:36 nM

    B-Raf (V600E), Kd:14 nM

  • C-Raf/Raf-1

    C-Raf, Kd:39 nM
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 BRAFV600E 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 BRAFV600E. It exhibits potent binding (BRAFV600E Kd = 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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.93mL

0.39mL

0.19mL

9.66mL

1.93mL

0.97mL

19.33mL

3.87mL

1.93mL
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.