Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase

  • Bioorg Med Chem Lett. 2013 Jun 1;23(11):3186-94. doi: 10.1016/j.bmcl.2013.04.001.
Peter S Dragovich  1 ,  Benjamin P Fauber ,  Laura B Corson ,  Charles Z Ding ,  Charles Eigenbrot ,  HongXiu Ge ,  Anthony M Giannetti ,  Thomas Hunsaker ,  Sharada Labadie ,  Yichin Liu ,  Shiva Malek ,  Borlan Pan ,  David Peterson ,  Keith Pitts ,  Hans E Purkey ,  Steve Sideris ,  Mark Ultsch ,  Erica VanderPorten ,  BinQing Wei ,  Qing Xu ,  Ivana Yen ,  Qin Yue ,  Huihui Zhang ,  Xuying Zhang
Affiliations
PMID: 23628333 DOI: 10.1016/j.bmcl.2013.04.001
Abstract

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 μM). 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 μM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.