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Pexmetinib

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Chemical Structure| 945614-12-0 同义名 : ARRY-614
CAS号 : 945614-12-0
货号 : A189540
分子式 : C31H33FN6O3
纯度 : 99%+
分子量 : 556.63
MDL号 : MFCD28502055
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: 120 mg/mL(215.58 mM)，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：
生物活性
靶点

  • Tie-2

  • p38 MAPK
描述 Acute myeloid leukemia and myelodysplastic syndromes are incurable hematologic neoplasms in which the angiopoietin-1/Tie-2 pathway is over-activated. Pexmetinib is a small molecular, orally bioavailable inhibitor of the angiopoietin-1 receptor Tie-2 and the pro-inflammatory kinase p38 MAPK. The IC50 values of pexmetinib against Tie-2, p38 MAPK α and β were 1, 35, and 36 nM, respectively. Pexmetinib also inhibited phospho-Tie-2 and phospho-p38 in HEK-Tie2 cells with IC50 values of 16 and 1 nM, respectively. It was predicted that the plasma concentrations of pexmetinib to achieve 50% inhibition for phospho-Tie-2 and phospho-p38 in human blood samples were 2282 and 172 nM, respectively. In TNF-α-treated leukemic KG1 cells, pexmetinib at 10 nM completely abrogated TNF-α-induced activation of p38 MAPK, MAPKAPK2 and EIF4E. In primary CD34+ stem cells, pexmetinib at 0.1 μM significantly reversed the myelosuppressive effects induced by TNF-α[3]. Mechanism: Pexmetinib is a type 2 kinase inhibitor that binds both Tie-2 and p38 MAPK in the “DFG-out” conformation[3].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.80mL

0.36mL

0.18mL

8.98mL

1.80mL

0.90mL

17.97mL

3.59mL

1.80mL
参考文献

[1]Bachegowda L, Morrone K, et al. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res. 2016 Aug 15;76(16):4841-4849.

[2]Wollenberg LA, Corson DT, et al. An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614). Clin Pharmacol. 2015 Sep 30;7:87-95.

[3]Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S, Bhagat T, Bhattacharyya S, Assal A, Shastri A, Gordon-Mitchell S, Pellagatti A, Boultwood J, Schinke C, Yu Y, Guha C, Rizzi J, Garrus J, Brown S, Wollenberg L, Hogeland G, Wright D, Munson M, Rodriguez M, Gross S, Chantry D, Zou Y, Platanias L, Burgess LE, Pradhan K, Steidl U, Verma A. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res. 2016 Aug 15;76(16):4841-4849. doi: 10.1158/0008-5472.CAN-15-3062. Epub 2016 Jun 10. PMID: 27287719; PMCID: PMC5398415.