Biological Activity
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].
References
[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.
