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Targeting allosteric regulation of cancer metabolism

Nature Chemical Biology volume 18, pages 441–450 (2022)Cite this article

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Abstract

Metabolic reprogramming is observed across all cancer types. Indeed, the success of many classic chemotherapies stems from their targeting of cancer metabolism. Contemporary research in this area has refined our understanding of tumor-specific metabolic mechanisms and has revealed strategies for exploiting these vulnerabilities selectively. Based on this growing understanding, new small-molecule tools and drugs have been developed to study and target tumor metabolism. Here, we highlight allosteric modulation of metabolic enzymes as an attractive mechanism of action for small molecules that target metabolic enzymes. We then discuss the mechanistic insights garnered from their application in cancer studies and highlight the achievements of this approach in targeting cancer metabolism. Finally, we discuss technological advances in drug discovery for allosteric modulators of enzyme activity.

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Fig. 1: Allosteric regulation of glycolysis and adjacent pathways.
Fig. 2: Glutamine- and lipid-metabolism pathways and allosteric inhibitors.
Fig. 3: Allosteric binding in glutamine metabolism and adjacent pathways.
Fig. 4: Allosteric inhibition of methionine metabolism.
Fig. 5: Proteomic techniques for discovering allosteric modulators.

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Acknowledgements

C.A.L. received support from the NCI (R37CA237421, R01CA248160 and R01CA244931). D.M.K. received support from the George E. Hewitt Foundation for Medical Research.

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  1. Daniel M. Kremer

    Present address: Department of Chemistry, the Scripps Research Institute, La Jolla, CA, USA

  2. These authors contributed equally: Daniel M. Kremer, Costas A. Lyssiotis.

Authors and Affiliations

  1. Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Daniel M. Kremer & Costas A. Lyssiotis

  2. Graduate Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA

    Daniel M. Kremer

  3. Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA

    Costas A. Lyssiotis

  4. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Costas A. Lyssiotis

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D.M.K. and C.A.L. contributed to conceptualization, investigation, writing, review and editing. C.A.L. provided supervision.

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Correspondence to Costas A. Lyssiotis.

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Competing interests

C.A.L. has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox-control pathways in cancer and targeting the GOT1 pathway as a therapeutic approach.

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Kremer, D.M., Lyssiotis, C.A. Targeting allosteric regulation of cancer metabolism. Nat Chem Biol 18, 441–450 (2022). https://doi.org/10.1038/s41589-022-00997-6

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