Dabrafenib Mesylate (GSK-2118436)
(Synonyms: 甲磺酸达拉非尼; GSK2118436 Mesylate; GSK 2118436B) 目录号 : GC12486
A Raf kinase inhibitor
Cas No.:1195768-06-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
M257 wild-type BRAF, LCP BRAFV600R and WM266 BRAFV600D melanoma cell lines. |
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Preparation method |
Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
3-100 nM; 72 h |
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Applications |
Dabrafenib remarkably inhibits cell proliferation and phosphorylated ERK in both melanoma cell lines carrying a mutated BRAF. |
| Animal experiment [2]: | |
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Animal models |
Female CD1 nu/nu mice xenografted BRAFV600E (A375P) human tumor. |
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Dosage form |
30 mg/kg; 14 days; dosed orally once daily. |
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Preparation method |
0.5% hydroxypropylmethylcellulose, 0.2% Tween 80 in pH 8.0 distilled water; 0.2 mL per 20 g of bodyweight. |
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Applications |
Dabrafenib is orally bioavailable, reduces pERK and inhibits tumor growth. Dabrafenib reduces pERK and Ki67 by 89% and 28% respectively and increases p27 by 54%. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Gentilcore G, Madonna G, Mozzillo N, et al. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer, 2013, 13: 17. [2]. King AJ, Arnone MR, Bleam MR, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One, 2013, 8(7): e67583. | |
GSK2118436 is a selective BRAF V600E inhibitor. BRAF encodes a proto-oncogene B-Raf also known as serine/threonine protein kinase B-Raf. It is critical in regulating the MAPK/ERK signaling pathway. BRAF mutations frequently occur in many human cancers. [1, 2] BRAF V600E mutant is constitutively active, allowing MAPK/ERK activation independent of upstream cues. [3]
GSK2118436 binds to Raf family kinases and inhibits their activity. It is highly selective against B-Raf V600E with IC50 of 0.8 nM, compared to wild type B-Raf and c-Raf with IC50s of 3.2 nM and 5.0 nM, respectively. [4]
GSK2118436 treatment shows selective inhibition of MAPK/ERK activation, proliferation, transformation and tumorigenicity. FDA approved GSK2118436 as a single agent treatment for advanced melanoma with BRAF V600E mutation on May 30, 2013.
GSK2118436 can be taken orally.
References:
[1]Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab. 2003; 88 (9): 4393–7.
[2]Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by pyrosequencing. Pathology 2008; 40 (3): 295–8.
[3]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949-954.
[4]Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014; 124(3): 1406-17.
| Cas No. | 1195768-06-9 | SDF | |
| 别名 | 甲磺酸达拉非尼; GSK2118436 Mesylate; GSK 2118436B | ||
| 化学名 | N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;methanesulfonic acid | ||
| Canonical SMILES | CC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F.CS(=O)(=O)O | ||
| 分子式 | C24H24F3N5O5S3 | 分子量 | 615.67 |
| 溶解度 | ≥ 30.75 mg/mL in DMSO, ≥ 2.74 mg/mL in EtOH with ultrasonic and warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6242 mL | 8.1212 mL | 16.2425 mL |
| 5 mM | 0.3248 mL | 1.6242 mL | 3.2485 mL |
| 10 mM | 0.1624 mL | 0.8121 mL | 1.6242 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Abstract
The pharmacokinetic parameters of dabrafenib, an inhibitor of human BRAF, CRAF and mutant BRAF kinases, have determined in four patients with BRAF mutation-positive solid tumors, in which the least squares mean absolute bioavailability, median T(max) after oral administration, the geometric mean terminal half-life, the geometric mean clearance and volume of distribution after IV administration were 94.5%, 2.0 hours, 4.8 hours, 12.0 L/h and 45.5 L respectively.
Abstract
Dabrafenib has been assessed for IC and EC patterns of response and progression in the treatment of patients with active melanoma brain metastases.
Abstract
The population pharmacokinetics of dabrfenib, a BRAF inhibitor, were characterized, in which steady state was achieved in 14 days following a 150 mg BID dose with total clearance, induction half-life and pre-dose concentration of 34.3 L/h, 67 hours and 46.6 ng/mL respectively. Capsule shell, sex and weight did affect dabrafenib exposure; while age, renal and hepatic impairment didn’t.
Abstract
Dabrafenib exhibits efficacy against BRAF V600E-mutated melanoma, non-V600E BRAF-mutated disease and brain metastases, where 50% response rate and 6 months progression-free survival were observed in dabrafenib-treated melanoma patients with BRAF V600E mutations. The combination of dabrafenib and trametinib showed synergistic effects to improve both the progression-free survival and overall survival of melanoma patients.
Abstract
Clinical development and characteristics of dabrafenib were summarized and compared to vemurafenib.