Design,synthesis and evaluation of d-amino acid-containing peptidomimetics targeting the polo-box domain of polo-like kinase 1 |
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| Institution: | 1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;2. Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China;3. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;4. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China;1. University Grenoble Alpes, DPM UMR 5063, F-38041 Grenoble, France;2. CNRS, DPM UMR 5063, F-38041 Grenoble, France;3. Département de Biochimie, Toxicologie et Pharmacologie, CHU de Grenoble Site Nord - Institut de Biologie et de Pathologie, F-38041 Grenoble, France;4. University Grenoble Alpes, Laboratory of Hypoxy Physiopathology Study Inserm U1042, 38700 La Tronche, France;1. Institut de Chimie des Substances Naturelles, CNRS, ICSN UPR2301, Université Paris-Saclay, 91198, Gif-sur-Yvette, France;2. UMR CNRS 8126, Univ. Paris Sud, Université Paris-Saclay, Institut Gustave Roussy, 114 rue Edouard-Vaillant, 94805, Villejuif Cedex, France;1. Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland;2. Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, 50-383 Wroclaw, Poland;3. Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan;4. School of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, West Midlands B15 2TT, UK;1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo namesti 2, Prague 16610, Czech Republic;2. Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic;3. Miltenyi Biotec GmbH, Friedrich-Ebert-Straße 68, D-51429 Bergisch Gladbach, Germany |
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| Abstract: | A series of d-amino acid-containing peptidomimetics were designed, synthesized as novel polo-like kinase 1 (Plk1) polo-box domain (PBD) inhibitors based on the reported peptide Plk1 PBD inhibitor. Their inhibitory activity to Plk1, Plk2, and Plk3 PBD were evaluated using our fluorescence polarization (FP) assay. Compound 18 bound to Plk1 PBD with IC50 of 0.80 μM and showed nearly no inhibition to Plk2 PBD or Plk3 PBD at 100 μM. Compound 18 induced Hela cells to undergo apoptosis by increasing the ratio of the cells at the G2/M phase by decreasing the neosynthesized proteins in a dose-dependent manner from 50 to 150 μM. Compound 18 showed improved stability in rat plasma compared to l-peptide inhibitor LHSpTA. These novel d-amino acid modified selective Plk1 PBD inhibitors may provide new lead compounds for further optimization. |
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| Keywords: | Polo like kinase 1 Polo-box domain Inhibitors Anticancer |
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