Abstract
To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD+ and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment. Cancer Res; 77(4); 937-48. ©2017 AACR.
Highlights
Dividing cells depend on a high and steady supply of 10-formyltetrahydrofolate to sustain several vital anabolic reactions, for example the synthesis of purines
Activity and inhibition of MTHFD2 and MTHFD1 Human MTHFD2 and the DC domain of MTHFD1 were purified from bacteria and activity was determined using the NAD(P)H-Glo assay (Promega)
IC50 values of LY345899 were determined to 663 nmol/L for MTHFD2 (n 1⁄4 7) and 96 nmol/L for MTHFD1 (n 1⁄4 2; Fig. 2)
Summary
Dividing cells depend on a high and steady supply of 10-formyltetrahydrofolate to sustain several vital anabolic reactions, for example the synthesis of purines. Targeting this pathway is one way to target cancer cells, and one successful example is the antifolate drug methotrexate that has been used in cancer therapies since the 1950s [1]. The folate-dependent one-carbon metabolism is highly compartmentalized between cytoplasm and mitochondria [2, 3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Depending on the different redox environments in the mitochondria and cytoplasm, the metabolic flow occurs mostly in the clockwise direction in the
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