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

• DOI: 10.1016/j.bmcl.2014.06.076
• Publication Date: 2014-07-02T06:37:08Z
• Authors: Peter S. Dragovich; Benjamin P. Fauber; Jason Boggs; Jinhua Chen; Laura B. Corson; Charles Z. Ding; Charles Eigenbrot; HongXiu Ge; Anthony M. Giannetti; Thomas Hunsaker; Sharada Labadie; Chiho Li; Yichin Liu; Yingchun Liu; Shuguang Ma; Shiva Malek; David Peterson; Keith E. Pitts; Hans E. Purkey; Kirk Robarge; Laurent Salphati; Steve Sideris; Mark Ultsch; Erica VanderPorten; Jing Wang; BinQing Wei; Qing Xu; Ivana Yen; Qin Yue; Huihui Zhang; Xuying Zhang; Aihe Zhou
• Keywords: Lactate dehydrogenase A; IC50; High-Throughput Screening

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%).