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].
Pexmetinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Ba/F3T315I cells
10 µM
Screening for selective inhibition of ABL1T315I, pexmetinib showed specific cytotoxicity
Leukemia. 2024 Aug;38(8):1843-1847.
Healthy CD34+ cells
0.1μM
14 days
Assess the reversal effect of pexmetinib on TNF-α-induced myelosuppression
Cancer Res. 2016 Aug 15;76(16):4841-4849.
MDA-MB-231 cells
0–60 μM
48 and 96 hours
Pexmetinib inhibited migration and invasion of MDA-MB-231 cells.
J Bone Oncol. 2022 Jun 11;35:100439.
Bone marrow macrophage cells (BMMs)
0, 0.1, 0.2, 0.4 μM
5 days
Pexmetinib inhibited RANKL-induced osteoclast formation and bone resorption.
J Bone Oncol. 2022 Jun 11;35:100439.
Pexmetinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
CD-1 mice and nu/nu NCr mice
HEK-Tie2 xenograft model
Oral
varying doses
Single dose
Assess the in vivo inhibitory effect of pexmetinib on p-p38 and pTie2
Cancer Res. 2016 Aug 15;76(16):4841-4849.
BALB/c mice
EMT6 and CT26 syngeneic models
Oral
30mg/kg
Once daily for 21 days
Evaluate the antitumor efficacy of pexmetinib in combination with immune checkpoint inhibitors
Res Sq [Preprint]. 2023 Aug 19:rs.3.rs-3183496
BALB/c nu/nu mice
Breast cancer bone metastasis induced osteolysis model
Intraperitoneal injection
10 mg/kg
Every three days for one month
Pexmetinib suppressed breast cancer cell-induced osteolytic lesions.
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