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J Med Chem. 2017 Nov 22;60(22):9184-9204. doi: 10.1021/acs.jmedchem.7b00941. Epub 2017 Nov 9.

Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).

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National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
Beryllium Discovery Corp. , 7869 Day Road West, Bainbridge Island, Washington 98110, United States.
Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute , 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
Abramson Cancer Center, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania , Philadephia, Pennsylvania 19104, United States.


We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.

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