4.5 Article

Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase

Journal

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 20, Pages 5533-5539

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.08.060

Keywords

Lactate dehydrogenase; X-ray crystal structure; Pyrazine; Tumor metabolism

Funding

  1. Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]

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A 2-amino-5-aryl-pyrazine was identified as an inhibitor of human lactate dehydrogenase A (LDHA) via a biochemical screening campaign. Biochemical and biophysical experiments demonstrated that the compound specifically interacted with human LDHA. Structural variation of the screening hit resulted in improvements in LDHA biochemical inhibition and pharmacokinetic properties. A crystal structure of an improved compound bound to human LDHA was also obtained and it explained many of the observed structure-activity relationships. (C) 2013 Elsevier Ltd. All rights reserved.

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