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  • Title: Design, synthesis, and evaluation of non-ATP-competitive small-molecule Polo-like kinase 1 (Plk1) inhibitors.
    Author: Chen DX, Huang J, Liu M, Xu YG, Jiang C.
    Journal: Arch Pharm (Weinheim); 2015 Jan; 348(1):2-9. PubMed ID: 25430493.
    Abstract:
    A series of small-molecule Plk1 inhibitors targeting the substrate-binding pocket were designed through rational drug design for the first time. The designed compounds were synthesized and their activities were evaluated in vitro. Some of the targeted compounds showed potent Plk1 inhibitory activities and anti-proliferative characters. Particularly, 5i showed Plk1 inhibitory activity with an IC50 value of 0.68 µM. Compound 5i also showed cell growth inhibitory activity on HeLa cells with an IC50 value of 0.51 µM, which is about four times more potent compared to thymoquinone. The mechanism of action suggested that 5i was an ATP-independent and substrate-dependent Plk1 inhibitor. Compound 5i demonstrated excellent Plk1 inhibitory selectivity against Plk2, Plk3, and five serine/threonine and tyrosine kinases. Our discovery and structure-activity relationship study may provide useful lead compounds for further optimization of non-ATP-competitive Plk1 inhibitors.
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