| Literature DB >> 25037916 |
Peter S Dragovich1, Benjamin P Fauber2, Jason Boggs2, Jinhua Chen3, Laura B Corson2, Charles Z Ding3, Charles Eigenbrot2, HongXiu Ge3, Anthony M Giannetti2, Thomas Hunsaker2, Sharada Labadie2, Chiho Li3, Yichin Liu2, Yingchun Liu3, Shuguang Ma2, Shiva Malek2, David Peterson2, Keith E Pitts2, Hans E Purkey2, Kirk Robarge2, Laurent Salphati2, Steve Sideris2, Mark Ultsch2, Erica VanderPorten2, Jing Wang3, BinQing Wei2, Qing Xu3, Ivana Yen2, Qin Yue2, Huihui Zhang3, Xuying Zhang3, Aihe Zhou2.
Abstract
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%).Entities:
Keywords: Glycolysis; Lactate dehydrogenase; Tumor metabolism; X-ray crystal structure
Mesh：
Substances：
Year: 2014 PMID： 25037916 DOI： 10.1016/j.bmcl.2014.06.076
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823