Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3764-71. doi: 10.1016/j.bmcl.2014.06.076. Epub 2014 Jul 1.


A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 μM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 μM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).

Keywords: Glycolysis; Lactate dehydrogenase; Tumor metabolism; X-ray crystal structure.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Cyclohexanones / administration & dosage
  • Cyclohexanones / chemistry
  • Cyclohexanones / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / administration & dosage
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology*


  • Cyclohexanones
  • Enzyme Inhibitors
  • Sulfhydryl Compounds
  • L-Lactate Dehydrogenase