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

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

  • Cancer Res. 2017 Feb 15;77(4):937-948. doi: 10.1158/0008-5472.CAN-16-1476.
Robert Gustafsson 1,  Ann-Sofie Jemth 2,  Nina M S Gustafsson 2,  Katarina Färnegårdh 3,  Olga Loseva 2,  Elisée Wiita 2,  Nadilly Bonagas 2,  Leif Dahllund 4,  Sabin Llona-Minguez 2,  Maria Häggblad 5,  Martin Henriksson 2,  Yasmin Andersson 4,  Evert Homan 2,  Thomas Helleday 6,  Pål Stenmark 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • 2 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 3 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
  • 4 Drug Discovery and Development Platform, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology, Solna, Sweden.
  • 5 Biochemical and Cellular Screening, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • 6 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. stenmark@dbb.su.se thomas.helleday@scilifelab.se.
  • 7 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. stenmark@dbb.su.se thomas.helleday@scilifelab.se.
PMID: 27899380 DOI: 10.1158/0008-5472.CAN-16-1476
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.

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