2. Academic Validation
  3. Identification of indole-3-carboxylic acids as non-ATP-competitive Polo-like kinase 1 (Plk1) inhibitors

Identification of indole-3-carboxylic acids as non-ATP-competitive Polo-like kinase 1 (Plk1) inhibitors

  • Bioorg Med Chem Lett. 2015 Feb 1;25(3):431-4. doi: 10.1016/j.bmcl.2014.12.060.
Meng Liu 1,  Jie Huang 2,  Dong-Xing Chen 1,  Cheng Jiang 3
Affiliations

Affiliations

  • 1 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.
  • 2 Gansu Institute for Food and Drug Control, Yinan road 7, Lanzhou 730070, China.
  • 3 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: [email protected].
PMID: 25556101 DOI: 10.1016/j.bmcl.2014.12.060
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.

Keywords

Inhibitors; Non-ATP-competitive; Polo-like kinase 1; Structure–activity relationship.

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