1. Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
- Author
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Sabin Llona-Minguez, Katarina Färnegårdh, Leif Dahllund, Maria Häggblad, Nina M. S. Gustafsson, Yasmin Andersson, Pål Stenmark, Nadilly Bonagas, Ann-Sofie Jemth, Thomas Helleday, Olga Loseva, Elisee Wiita, Robert Gustafsson, Martin Henriksson, and Evert Homan
- Subjects
0301 basic medicine ,Purine ,Cancer Research ,Leucovorin ,Methenyltetrahydrofolate Cyclohydrolase ,Biology ,Thymidylate synthase ,Minor Histocompatibility Antigens ,03 medical and health sciences ,chemistry.chemical_compound ,Folic Acid ,0302 clinical medicine ,Downregulation and upregulation ,Oxidoreductase ,medicine ,Humans ,Enzyme Inhibitors ,Binding site ,Methylenetetrahydrofolate Dehydrogenase (NADP) ,chemistry.chemical_classification ,Binding Sites ,Cancer ,NAD ,medicine.disease ,Mitochondria ,030104 developmental biology ,Enzyme ,Oncology ,Biochemistry ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Protein Multimerization ,Crystallization - 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.
- Published
- 2017