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Design, Synthesis, and Evaluation of Non‐ATP‐Competitive Small‐Molecule Polo‐Like Kinase 1 (Plk1) Inhibitors
Author(s) -
Chen DongXing,
Huang Jie,
Liu Meng,
Xu YunGen,
Jiang Cheng
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201400294
Subject(s) - plk1 , polo like kinase , kinase , ic50 , chemistry , lead compound , small molecule , hela , biochemistry , serine , structure–activity relationship , threonine , substrate (aquarium) , in vitro , enzyme , biology , cell , cell cycle , ecology
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 IC 50 value of 0.68 µM. Compound 5i also showed cell growth inhibitory activity on HeLa cells with an IC 50 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.