Design,synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors |
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| Institution: | 1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China;2. University of Science and Technology of China, Hefei, Anhui 230036, PR China;3. CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei Anhui 230031, PR China;4. Department of Chemistry, University of California-Riverside, 900 University Ave., Riverside, CA 92521, USA;5. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02115, USA;6. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA;7. Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, PR China;8. Hefei Science Center, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China;1. Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany;2. Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany;1. School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan;2. Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, No. 321, Section 2, Guangfu Road, Hsinchu 30011, Taiwan;3. Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung 43301, Taiwan;4. Department of Life Science, College of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States;2. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, United States;3. Division of Hematology and University of Colorado, Aurora, CO, 80045, United States;1. College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea;2. Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung-Hee University, Seoul 130-701, Republic of Korea |
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| Abstract: | A series of thienopyridinone derivatives was designed and synthesized as inhibitors of checkpoint kinase 1 (Chk1). Most of them exhibited moderate to good Chk1 inhibitory activities. Among them, compounds 8q, 8t, and 8w with excellent Chk1 inhibitory activities (IC50 values of 4.05, 6.23, and 2.33 nM, respectively) displayed strong synergistic effects with melphalan, a DNA-damaging agent in the cell-based assay. Further kinase profiling indicated that compound 8t was highly selective against CDK2/cyclinA, Aurora A, and PKC. |
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| Keywords: | Chk1 inhibitor Thienopyridinones Antitumor Cell synergy |
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