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Pexmetinib (ARRY-614)

Catalog No.
dual inhibitor of p38 MAPK and Tie2/Tek receptor tyrosine kinase
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Pexmetinib (ARRY-614) is a potent inhibitor of cytokine synthesis, via the dual inhibition of p38 mitogen-activated protein kinase (MAPK), and Tie2/Tek receptor tyrosine kinase. The in vitro IC50 values of ARR Y-614 for both Tie2 and p38 mitogen-activated protein kinase are 1000 ng/mL and 100 ng/mL, respectively [1, 2].

p38 is a group of mitogen-activated protein kinases. MAPKs are activated by the dual phosphorylation of Tyr and Thr residues in the Thr-Xaa-Tyr motif in subdomain VIII. Data indicated that p38 MAPK may mediate signaling to the nucleus [3].

ARRY-614 is active against MAPK and Tie2/Tek receptor tyrosine kinase in cells. In primary human bone marrow stromal cells, ARRY-614 inhibited basal cytokines with an IC50 value ranging from 50-100 nM [4].

In dose escalation or expansion cohorts, treatment with ARRY-614 either once daily or twice daily was applied to forty-five patients. ARRY-614 reduced the levels of circulating biomarkers and the p38 MAPK activation of bone marrow [1]. In ex vivo stimulated human whole blood, LPS-induced cytokines was inhibited by ARRY-614 with an IC50 value ranging from 50-120 nM. ARRY-614 inhibited the release of IL-6 from SEA- or LPS-challenged mice with an ED50 value less than 10 mg/kg. Combining ARRY-614 with lenalidomide inhibited both pro-inflammatory cytokines and tumor growth in vivo with higher potency, compared with either agent alone [4].

[1].  Garcia-Manero G, Khoury HJ, Jabbour E, et al. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clinical Cancer Research, 2015, 21(5): 985-994.
[2].  Wollenberg LA, Corson DT, Nugent CA, 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). Clinical pharmacology: advances and applications, 2015, 7: 87.
[3].  Raingeaud J, Whitmarsh AJ, Barrett T, et al. MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Molecular and cellular biology, 1996, 16(3): 1247-1255.
[4].  Winski S, Humphries M, Yeh T, et al. Activity of ARRY-614, an inhibitor of p38 map kinase and angiogenic targets, in hematologic malignancies. Cancer Research, 2009, 69(9 Supplement): 331-331.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
Cas No.945614-12-0
Solubility≥107.6 mg/mL in DMSO,insoluble in H2O, ≥113 mg/mL in EtOH
Chemical Name1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(5-fluoro-2-((1-(2-hydroxyethyl)-1H-indazol-5-yl)oxy)benzyl)urea
SDFDownload SDF
Canonical SMILESCC1=CC=C(N2C(NC(NCC3=CC(F)=CC=C3OC4=CC=C5C(C=NN5CCO)=C4)=O)=CC(C(C)(C)C)=N2)C=C1
Shipping ConditionEvaluation sample solution: ship with blue ice. All other available sizes: ship with RT, or blue ice upon request.
General tipsFor obtaining a higher solubility, please warm the tube at 37°C and shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.

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