In vitro cytotoxicity screening to identify novel anti-osteosarcoma therapeutics targeting pyruvate dehydrogenase kinase 2 |
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| Affiliation: | 1. Clinical Laboratory, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China;2. Gansu Provincial Hospital, Lanzhou, Gansu 730000, China;3. The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China;1. Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;3. PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan;4. CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan;1. Department of Pathology and Laboratory Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;2. Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;3. David Geffen School of Medicine at UCLA, Volunteering Program, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;4. Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;5. UCLA AIDS Institute, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;6. Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA;7. The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA;1. Ufa Institute of Chemistry, Ufa Federal Research Centre of RAS, 71, Prospect Oktyabrya, Ufa 450054, Russian Federation;2. Department of Medical Laboratory Science and Biotechnology, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC;3. Department of Biotechnology, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC;4. School of Chinese Medicine, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC;5. Division of Hepato-gastroenterology, Department of Internal Medicine, China Medical University Hospital, 2, Yude Rd., Taichung 40447, Taiwan, ROC;6. Chinese Medicine Research Center, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC;1. Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA;2. Department of Biological Sciences, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA;3. High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA;4. Clare Associates LLC, Skokie, IL 60077, USA;1. Damascus University, College of Medicine, Syrian Arab Republic;2. Head of Nephrology Department and Kidney Transplant Unit AUH, Damascus University, College of Medicine, Syrian Arab Republic;6. Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China |
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| Abstract: | Pyruvate dehydrogenase kinases (PDKs) act as negative modulator of mitochondrial pyruvate dehydrogenase complex (PDC) and play a crucial role in the regulation of oxidative glycolysis, which recently have been considered as a potential drug target for varying types of cancer and diabetes. Herein, we describe the discovery and biological validation of novel anti-osteosarcoma therapeutics targeting PDK2. We identified 14 anti-osteosarcoma compounds from an in-house small molecule library, which were then evaluated in a PDK2 kinase inhibition assay. We found that compounds with 2-((4-oxo-6-((4-phenylpiperazin-1-yl)methyl)-4H-pyran-3-yl)oxy)acetamide moiety showed promising inhibitory potencies to PDK2. Especial for 12, which bound to PDK2 with a Kd value of 2.3 µM, and inhibited PDK2 activity with an EC50 value of 1.1 µM. In addition, 12 selectively inhibited PDK2, the selectivity indexes are 10.6, 22.0, and 60.9 for PDK2 as compared to PDK1, 2 and 4, respectively. The MTT assay suggested that 12 reduced MG-63 cancer cell proliferation with an IC50 value of 4.7 µM. All these observations indicated that 12 was a novel anti-osteosarcoma therapeutic, which deserved for further investigation. |
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| Keywords: | Cancer metabolism Anticancer Pyruvate dehydrogenase kinase 2 |
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