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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].

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