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.
Peter S Dragovich  1 ,  Benjamin P Fauber  2 ,  Jason Boggs  2 ,  Jinhua Chen  3 ,  Laura B Corson  2 ,  Charles Z Ding  3 ,  Charles Eigenbrot  2 ,  HongXiu Ge  3 ,  Anthony M Giannetti  2 ,  Thomas Hunsaker  2 ,  Sharada Labadie  2 ,  Chiho Li  3 ,  Yichin Liu  2 ,  Yingchun Liu  3 ,  Shuguang Ma  2 ,  Shiva Malek  2 ,  David Peterson  2 ,  Keith E Pitts  2 ,  Hans E Purkey  2 ,  Kirk Robarge  2 ,  Laurent Salphati  2 ,  Steve Sideris  2 ,  Mark Ultsch  2 ,  Erica VanderPorten  2 ,  Jing Wang  3 ,  BinQing Wei  2 ,  Qing Xu  3 ,  Ivana Yen  2 ,  Qin Yue  2 ,  Huihui Zhang  3 ,  Xuying Zhang  3 ,  Aihe Zhou  2
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3. WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
PMID: 25037916 DOI: 10.1016/j.bmcl.2014.06.076
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%).

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