Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 11, Pages 3186-3194Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.04.001
Keywords
Lactate dehydrogenase; X-ray crystal structure; Glycolysis; Tumor metabolism
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Funding
- Office of Science, Office of Basic Energy Sciences, of the U. S. Department of Energy [DE-AC02-05CH11231]
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A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50 = 8.1 mu M). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.48 mu M). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships. (C) 2013 Elsevier Ltd. All rights reserved.
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