The objective of the work proposed herein is to develop novel inhibitors of the human enzyme lactate dehydrogenase A (LDH-A). LDH-A catalyzes the conversion of pyruvate to lactate, the final step in the glycolytic pathway. Although a few LDH-A inhibitors have been reported, no compounds are suitable for further development (ie, potent, specific, synthetically tractable, and metabolically stable). In preliminary results w have discovered a novel class of LDH-A inhibitors, the N-hydroxyindoles (NHIs). These compounds inhibit LDH-A in vitro, inhibit tumor growth in vivo, and we have collected multiple lines of evidence indicating these compounds inhibit LDH-A in cells. We now wish to utilize this novel research tool, the NHI- based LDH-A inhibitors, to exploit the Warburg effect as a potential anticancer strategy. The Warburg effect is the tendency of cancer cells to rely on aerobic glycolysis instead of oxidative phosphorylation for energy production. Multiple lines of genetic data suggests that LDH-A inhibition could selectively induce death in cancer cells, and indeed as described in the preliminary results we have conducted multiple shRNA experiments that strongly suggest the inhibition of LDH-A will be an effective anticancer stragegy. Through the work proposed we intend to develop more potent NHIs as LDH-A inhibitors, assess their effect on cancer cells in culture, and evaluate them in murine tumor models. Through this work we intend to demonstrate that the inhibition of LDH-A is a tractable anticancer strategy, and to identify candidate experimental therapeutics.

Public Health Relevance

The inhibition of Lactate Dehydrogenase A (LDH-A) is a promising strategy for the treatment of cancer, unfortunately, no suitable LDH-A inhibitors exist. Described in this proposal is the development of a novel class of LDH-A inhibitors recently discovered by the PIs. These compounds will be optimized through chemical synthesis, tested for their effects on cancer cells in culture, and evaluated in two murine tumor models.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098453-01A1
Application #
8296996
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fabian, Miles
Project Start
2012-05-01
Project End
2016-02-28
Budget Start
2012-05-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$460,019
Indirect Cost
$86,303
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Rani, Reshma; Granchi, Carlotta (2015) Bioactive heterocycles containing endocyclic N-hydroxy groups. Eur J Med Chem 97:505-24
Xie, Han; Hanai, Jun-Ichi; Ren, Jian-Guo et al. (2014) Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab 19:795-809
Calvaresi, Emilia C; Hergenrother, Paul J (2013) Glucose conjugation for the specific targeting and treatment of cancer. Chem Sci 4:2319-2333
Calvaresi, Emilia C; Granchi, Carlotta; Tuccinardi, Tiziano et al. (2013) Dual targeting of the Warburg effect with a glucose-conjugated lactate dehydrogenase inhibitor. Chembiochem 14:2263-7
Granchi, Carlotta; Paterni, Ilaria; Rani, Reshma et al. (2013) Small-molecule inhibitors of human LDH5. Future Med Chem 5:1967-91
Granchi, Carlotta; Calvaresi, Emilia C; Tuccinardi, Tiziano et al. (2013) Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds. Org Biomol Chem 11:6588-96