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.

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