title: Design, synthesis, and evaluation of non-ATP-competitive small-molecule Polo-like kinase 1 (Plk1) inhibitors.
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.
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Dong-Xing
authors.initials: DX
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.forename: Yun-Gen
authors.initials: YG
authors.lastname: Xu
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
keywords: Non-ATP-competitive; Polo-like kinase 1; Rational drug design; Small-molecule; Structure-activity relationship