Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.

Gustafsson R, Jemth A, Gustafsson NMS, Färnegårdh K, Loseva O, Wiita E, Bonagas N, Dahllund L, Llona-Minguez S, Häggblad M, Henriksson M, Andersson Y, Homan E, Helleday T, Stenmark P

Cancer Res. 77 (4) 937-948 [2017-02-15; online 2016-12-03]

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.

Drug Discovery and Development (DDD) [Collaborative]

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PubMed 27899380

DOI 10.1158/0008-5472.CAN-16-1476

Crossref 10.1158/0008-5472.CAN-16-1476

0008-5472.CAN-16-1476

Medicinal Chemistry – Hit2Lead
Protein Expression and Characterization