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CAS No.: 945614-12-0

Pexmetinib Catalog No. CSN19212

Synonyms: ARRY-614

Pexmetinib is a potent, orally bioavailable, dual p38 MAPK/Tie-2 inhibitor with IC50 of 4 nM/18 nM in a HEK-293 cell line.

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技术信息

生物活性

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].
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
NCT01496495	Myelodysplastic Syndromes	Phase 1	Completed	-	United States, Florida ... more >> Moffitt Cancer Center Tampa, Florida, United States, 33612 United States, Georgia Emory University, Winship Cancer Institute Atlanta, Georgia, United States, 30322 United States, Ohio Cleveland Clinic Cleveland, Ohio, United States, 44195 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
NCT00916227	Myelodysplastic Syndromes	Phase 1	Completed	-	United States, Florida ... more >> Moffitt Cancer Center Tampa, Florida, United States, 33612 United States, Georgia Winship Cancer Institute Atlanta, Georgia, United States, 30322 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<

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.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.7965 mL
- 8.9826 mL
- 17.9652 mL
- 5 mM
- 0.3593 mL
- 1.7965 mL
- 3.5930 mL
- 10 mM
- 0.1797 mL
- 0.8983 mL
- 1.7965 mL

技术信息

CAS号

945614-12-0

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C31H33FN6O3

运输

蓝冰

分子量

556.63

别名

ARRY-614

溶解度

DMSO	450.0 mg/mL (808.4 mM)
Water	insoluble

动物实验配方

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