Identification of human lactate dehydrogenase A inhibitors with anti-osteosarcoma activity through cell-based phenotypic screening |
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| Affiliation: | 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;2. Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;3. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada;1. School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, PR China;2. Department of Radiology, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA;3. College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA;1. Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan;2. Institute for Chemical Research, Kyoto University Uji, Kyoto 611-0011, Japan;1. Arisan Therapeutics, 11189 Sorrento Valley Rd, Suite 104, San Diego 92121, CA, United States;2. Department of Pathology, and Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston 77555, TX, United States |
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| Abstract: | Human lactate dehydrogenase A plays a key role in the glycolytic process, the inhibition of the enzyme is therefore considered of interest in developing anticancer therapeutics. However, due to the highly polar nature of hLDHA binding pocket, it is very challenge to discover potent cellular active hLDHA inhibitor. Combined a cell-based phenotypic screening assay with a primary enzymatic assay, we discovered three cellular active hLDHA inhibitors, namely 38, 63, and 374, which reduced MG-63 cell proliferation with IC50 values of 6.47, 2.93, and 6.10 µM, respectively, and inhibited hLDHA with EC50 values of 3.03, 0.63, and 3.26 µM, respectively. |
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| Keywords: | Lactate dehydrogenase A Glycolysis Anticancer Cancer metabolism |
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