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

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

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Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.


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%).


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

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