title: Identification of indole-3-carboxylic acids as non-ATP-competitive Polo-like kinase 1 (Plk1) inhibitors.
abstract: A series of indole-3-carboxylic acids were designed as novel small molecular non-ATP-competitive Plk1 inhibitors. The designed compounds were synthesized and evaluated. Most of the targeted compounds showed potent Plk1 inhibitory activities and anti-proliferative characters. Particularly, 4f and 4g showed Plk1 inhibitory activity with IC50 values of 0.41 and 0.13μM, which were about 5 and 17 times more potent compared to thymoquinone, respectively. Compound 4g also showed inhibitory activity to HeLa and MCF-7 cell lines with IC50 values of 0.72 and 1.15μM, which was almost 3 and 4 times more potent than thymoquinone. Study of mechanism of action suggested that 4g was an ATP-independent and substrate-dependent Plk1 inhibitor. Moreover, 4g showed excellent Plk1 inhibitory selectivity against Plk2 and Plk3. Fluorescein isothiocyanate Annexin V/propidium iodide (PI) double-staining assay and western-blot results indicate that induction of apoptosis by 4g is involved in its anti-tumor activity. This study may provide a support for further optimization of non-ATP-competitive Plk1 inhibitors.
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy,China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Gansu Institute for Food and Drug Control, Yinan road 7, Lanzhou 730070, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy,China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: Dong-Xing
authors.initials: DX
authors.lastname: Chen
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy,China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Electronic address: jc@cpu.edu.cn.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D061986:MCF-7 Cells; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C012382:indole-3-carboxylic acid; C003466:thymoquinone
keywords: Inhibitors; Non-ATP-competitive; Polo-like kinase 1; Structure–activity relationship