American Association for Cancer Research
00085472can161476-sup-166907_1_supp_3668251_8h1wft.docx (16.43 kB)

Supplementary Table S1 from Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor

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journal contribution
posted on 2023-03-31, 00:43 authored by Robert Gustafsson, Ann-Sofie Jemth, Nina M.S. Gustafsson, Katarina Färnegårdh, Olga Loseva, Elisée Wiita, Nadilly Bonagas, Leif Dahllund, Sabin Llona-Minguez, Maria Häggblad, Martin Henriksson, Yasmin Andersson, Evert Homan, Thomas Helleday, Pål Stenmark

Buffers for MTHFD2 and MTHFD1 DC-domain lysis, purification and inhibition assay.


Swedish Research Council

Knut and Alice Wallenberg Foundation

Wenner-Gren Foundation

Swedish Society for Medical Research



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.