title: Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.
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.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Gustafsson
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Jemth
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nina M S
authors.initials: NM
authors.lastname: Gustafsson
authors.affiliation: Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Färnegårdh
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Loseva
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elisée
authors.initials: E
authors.lastname: Wiita
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nadilly
authors.initials: N
authors.lastname: Bonagas
authors.affiliation: Drug Discovery and Development Platform, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology, Solna, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Dahllund
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sabin
authors.initials: S
authors.lastname: Llona-Minguez
authors.affiliation: Biochemical and Cellular Screening, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Häggblad
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Henriksson
authors.affiliation: Drug Discovery and Development Platform, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology, Solna, Sweden.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Andersson
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Evert
authors.initials: E
authors.lastname: Homan
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. stenmark@dbb.su.se thomas.helleday@scilifelab.se.
authors.forename: Pål
authors.initials: P
authors.lastname: Stenmark
mesh_terms: D001665:Binding Sites; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000031:analogs & derivatives / Q000378:metabolism; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D055503:Protein Multimerization
chemical_list: D004791:Enzyme Inhibitors; D015778:Minor Histocompatibility Antigens; D009243:NAD; C010161:10-formyltetrahydropteroylglutamic acid; C032418:5,11-methenyltetrahydrohomofolate; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D045064:Methenyltetrahydrofolate Cyclohydrolase; D002955:Leucovorin