Selumetinib sulfate
(Synonyms: 司美替尼硫酸盐,AZD6244 sulfate; ARRY-142886 sulfate) 目录号 : GC38653
Selumetinib (AZD6244) 是一种高效选择性的，非 ATP 竞争性的 MEK1/2 抑制剂， 抑制 MEK1 的 IC50 为 14 nM。Selumetinib (AZD6244) 抑制 MEK1/2 磷酸化水平。
Cas No.:943332-08-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Selumetinib (AZD6244) is selective, non-ATP-competitive oral MEK1/2 inhibitor, with an IC50 of 14 nM for MEK1. Selumetinib (AZD6244) inhibits ERK1/2 phosphorylation.
Selumetinib (AZD6244) causes a time- and dose-dependent reduction in DNA synthesis and cell viability in primary, induces growth arrest and apoptosis associated with the inactivation of ERK in primary 2-1318 cells[1].Selumetinib (AZD6244) (1µM) shows anti-proliferative effects through G0/G1 arrest on H-441, H-1437 cells[2].Selumetinib (AZD6244) results in the growth inhibition of several cell lines containing B-Raf and Ras mutations but has no effect on a normal fibroblast cell line[3].
Selumetinib (AZD6244, 50 and 100 mg/kg, p.o.) decreases the growth rate of 4-1318 xenografts in a dose-dependent manner; AZD6244 when given at the dose of 50 mg/kg also significantly suppresses the growth of the 5-1318, 2-1318, 26-1004, and 29-1104 xenografts[1].Selumetinib (ARRY-142886, 10, 25, 50, or 100 mg/kg, p.o.) is capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions are also seen in a BxPC3 xenograft model[3].
[1]. [1].Huynh H, et al, Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Therapy, 2007, 6 (1), 138-146 [2]. [2].Garon EB, et al. Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Thera, 2010, 9 (7), 1985-1994. [3]. [3].Yeh TC, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res, 2007, 13 (5), 1576-1583.
| Cas No. | 943332-08-9 | SDF | |
| 别名 | 司美替尼硫酸盐,AZD6244 sulfate; ARRY-142886 sulfate | ||
| Canonical SMILES | OCCONC(C(C=C1C(N=CN1C)=C2F)=C2NC3=C(C=C(Br)C=C3)Cl)=O.O=S(O)(O)=O | ||
| 分子式 | C17H17BrClFN4O7S | 分子量 | 555.76 |
| 溶解度 | DMSO: 50 mg/mL (89.97 mM); Water: < 0.1 mg/mL (insoluble) | 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 | 1.7993 mL | 8.9967 mL | 17.9934 mL |
| 5 mM | 0.3599 mL | 1.7993 mL | 3.5987 mL |
| 10 mM | 0.1799 mL | 0.8997 mL | 1.7993 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。
Treating non-small cell lung cancer with Selumetinib: an up-to-date drug evaluation
Expert Opin Pharmacother 2020 Nov;21(16):1943-1953.PMID:32880495DOI:10.1080/14656566.2020.1798930.
Introduction: RAS-RAF-MEK-ERK signaling is implicated in tumor development by promoting cell proliferation and other cancer hallmarks. MEK1/2 kinases are up-regulated in the majority of human cancers due to activation of tyrosine kinase receptors, RAS proteins, BRAF kinase, or some other members of the MAPK pathway. Targeting of MEK1/2 kinases may counterbalance cancer progression. Areas covered: The authors analyze the scientific publications relevant to Selumetinib (AZD6244, ARRY-142886) systematically and provide their expert opinion. Expert opinion: Selumetinib is an oral selective allosteric inhibitor of MEK1 and MEK2 kinases. Single-agent Selumetinib is usually administered in hydrogen sulfate capsules 75 mg twice a day; combination with other therapeutic compounds may or may not require reduced dosing of this drug. The established dose for pediatric patients is 25 mg per square meter twice a day. Selumetinib was extensively evaluated in non-small cell lung cancer (NSCLC) patients. Studies utilizing this drug as a monotherapy did not confirm its efficacy toward NSCLC. A phase II trial showed that the addition of Selumetinib to docetaxel improved response rates and progression-free survival (PFS) in chemotherapy-pretreated KRAS-mutated NSCLC patients; however, a subsequent phase III study did not confirm these findings. There are several highly successful non-NSCLC Selumetinib trials involving, e.g., patients with neurofibromatosis type 1 related tumors and children with low-grade BRAF-driven gliomas.
Selumetinib: a promising pharmacologic approach for KRAS-mutant advanced non-small-cell lung cancer
Future Oncol 2013 Feb;9(2):167-77.PMID:23414467DOI:10.2217/fon.12.198.
Selumetinib is a potent and selective inhibitor of MEK1 and 2 that is currently being clinically developed for the treatment of several human malignancies. Initially administered as free-base suspension, a more convenient Hyd-sulfate capsule formulation has recently been developed. Phase I studies revealed that acneiform dermatitis was the dose-limiting toxicity of both the free-base and capsule formulation given two-times a day at the maximum tolerated doses of 100 and 75 mg, respectively, with the capsule formulation resulting into a significantly higher drug bioavailability. Importantly, as a MEK inhibitor, Selumetinib could be particularly effective in tumors with a hyperactivated Ras/Raf/MEK/ERK pathway, which might be the case of KRAS-mutant non-small-cell lung cancers (NSCLCs). Accordingly, a recent randomized Phase II study evaluating docetaxel plus Selumetinib or placebo in KRAS-mutant pretreated advanced NSCLC patients has demonstrated a significant improvement in terms of response rate, progression-free survival and patient-reported outcomes in favor of the combination arm. These positive results support further clinical evaluation of Selumetinib in NSCLC, and confirmatory ongoing and future trials will assess its role according to KRAS-mutation status and in combination regimens with other targeted agents.
Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT)
J Clin Oncol 2018 Apr 20;36(12):1232-1239.PMID:29528792DOI:10.1200/JCO.2017.74.1090.
Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to Selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive Selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the Selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with Selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (Selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of Selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.
Physiologically Based Biopharmaceutics Model for Selumetinib Food Effect Investigation and Capsule Dissolution Safe Space - Part I: Adults
Pharm Res 2023 Feb;40(2):387-403.PMID:36002614DOI:10.1007/s11095-022-03339-2.
Objective: A physiologically based biopharmaceutics model (PBBM) was developed to mechanistically investigate the effect of formulation and food on Selumetinib pharmacokinetics. Methods: Selumetinib is presented as a hydrogen sulfate salt, and in vitro and in vivo data were used to verify the precipitation rate to apply to simulations. Dissolution profiles observed for capsules and granules were used to derive product-particle size distributions for model input. The PBBM incorporated gut efflux and first-pass gut metabolism, based on intravenous and oral pharmacokinetic data, alongside in vitro data for the main enzyme isoform and P-glycoprotein efflux. The PBBM was validated across eight clinical scenarios. Results: The quality-control dissolution method for Selumetinib capsules was found to be clinically relevant through PBBM validation. A safe space for capsule dissolution was established using a virtual batch. The effect of food (low fat vs high fat) on capsules and granules was elucidated by the PBBM. For capsules, a lower amount was dissolved in the fed state due to a pH increase in the stomach followed by higher precipitation in the small intestine. First-pass gut extraction is higher for capsules in the fed state due to drug dilution in the stomach chyme and reduced concentration in the lumen. The enteric-coated granules dissolve more slowly than capsules after stomach emptying, attenuating the difference in first-pass gut extraction between prandial states. Conclusions: The PBBM was instrumental in understanding and explaining the different behaviors of the Selumetinib formulations. The model can be used to predict the impact of food in humans.
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2010 Jan-Feb;32(1):47-86.PMID:20383346doi
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