101. PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells
- Author
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Xinhua Qiao, Dan Zhao, Junyan Lu, Lunfeng Zhang, Zhen Gao, Hong Ding, Chang Chen, Hualiang Jiang, Cheng Luo, Yingying Zhao, Jiangmei Li, Panpan Zhang, and Jia Liu
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Mice, Nude ,Apoptosis ,Breast Neoplasms ,Thiophenes ,Biology ,Phosphatidylinositols ,Substrate Specificity ,Minor Histocompatibility Antigens ,Rats, Sprague-Dawley ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,Palmitoylation ,Animals ,Humans ,Phosphatidylinositol ,Viability assay ,Kinase activity ,Enzyme Inhibitors ,Protein kinase B ,Cell Proliferation ,Mice, Inbred BALB C ,Molecular Structure ,Kinase ,Cell growth ,Thiourea ,Molecular biology ,Xenograft Model Antitumor Assays ,Cell biology ,G2 Phase Cell Cycle Checkpoints ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Oncology ,chemistry ,MCF-7 Cells ,Female - Abstract
While phosphatidylinositol 4-kinase (PI4KIIα) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIα are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIα. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIα kinase activity (IC50 = 0.47 μmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIα. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIα knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIα. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIα. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G2–M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KIIα, the use of which will facilitate evaluations of PI4KIIα as a cancer therapeutic target. Cancer Res; 77(22); 6253–66. ©2017 AACR.
- Published
- 2017