EB-3D is a novel potent and selective choline kinase ChoKα inhibitor with an IC50 of 1 μM. EB-3D induces deregulation of the AMPK-mTOR pathway and apoptosis in leukemia T-cells and induces senescence in breast cancer cell lines through the activation of the metabolic sensorAMPK and the subsequent dephosphorylation of mTORC1 downstream targets.
Choline kinase (ChoK) catalyzes the phosphorylation of choline by ATP in the presence of Mg2+ to yield phosphocholine (PCho) and ADP. In humans, ChoKα1 and ChoKα2 derive from a single gene (chk-α) by alternative splicing. EB-3D, a potent and selective ChoKα inhibitor, shows an IC50 of 1 μM for human ChoKα1. In a panel of nine different human tumor-cell lines, EB-3D offered excellent antiproliferative activities against all cell lines with GI50 values ranging from 0.027 to 0.12 μM. The cell viability in the presence of EB-3D was also evaluated in Jurkat, HeLa and MDA-MB-231 cell lines. EB-3D significantly inhibited cell growth in three cell lines in a concentration-dependent manner. EB-3D induced a G1 arrest of the cell cycle, which occurred in a concentration-dependent manner in the three cell lines tested (Jurkat, MCF-7 and MDA-MB-231). Together with the G1 increase, a concomitant reduction was found in the S phase. Further, EB-3D at different concentrations after 72 h of incubation induced a modest increment in apoptotic cells only in Jurkat cells[1]. Experimental metastasis models obtained after the iv injection of murine E0771 or human MDA-MB-231 cells were treated with EB-3D at the dose of 2.5 mg/kg. After lung removal, the number of macrometastases as well as of micrometastases was significantly reduced in treated mice when compared with control lungs. In addition, a significant reduction of resected lung weight was appreciable after EB-3D treatment[2].
作用机制
The 1-benzyl-4-(dimethylamino)pyridinium fragment of EB-3D performs a strong π-cation interaction with the Cho binding site[1].
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