Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase |
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| Affiliation: | 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China;1. Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK;2. Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;3. Neuroscience Discovery, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;4. Musculoskeletal Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;1. College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul 151-742, Republic of Korea;2. New Drug Preclinical & Analytical Team, Life Science R&D Center, SK Chemicals, 310 Pangyo-ro, 463-400, Republic of Korea;3. College of Pharmacy and BK21 PLUS R-FIND Team, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 410-820, Republic of Korea;4. College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 420-743, Republic of Korea;1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA;4. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;5. Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA;1. Department of Pharmaceutical Science, Università degli Studi, Via Celoria 2, 20100 Milano, Italy;2. Department of Health Sciences, Università degli Studi, Via A. Di Rudinì 8, 20142 Milano, Italy;3. S. Paolo Hospital, Via A. Di Rudinì 8, 20142 Milano, Italy;1. Department of Chemistry, Middle Tennessee State University, 1301 Main St., Murfreesboro, TN, USA;2. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA |
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| Abstract: | A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50 = 30 nM). |
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| Keywords: | LDHA X-ray crystal structure Tumor metabolism |
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