title: Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site.
abstract: The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.
authors.affiliation: a Stratingh Institute for Chemistry, University of Groningen , Groningen , The Netherlands.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Masini
authors.affiliation: b Department of Biochemistry , School of Medicine and Biomedical Sciences, University at Buffalo, the State University of New York , Buffalo , NY , USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Birkaya
authors.affiliation: a Stratingh Institute for Chemistry, University of Groningen , Groningen , The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: van Dijk
authors.affiliation: a Stratingh Institute for Chemistry, University of Groningen , Groningen , The Netherlands.
authors.forename: Milon
authors.initials: M
authors.lastname: Mondal
authors.affiliation: c Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen , Groningen , The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Hekelaar
authors.affiliation: a Stratingh Institute for Chemistry, University of Groningen , Groningen , The Netherlands.
authors.forename: Manuel
authors.initials: M
authors.lastname: Jäger
authors.affiliation: c Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen , Groningen , The Netherlands.
authors.forename: Anke C
authors.initials: AC
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: b Department of Biochemistry , School of Medicine and Biomedical Sciences, University at Buffalo, the State University of New York , Buffalo , NY , USA.
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
authors.affiliation: a Stratingh Institute for Chemistry, University of Groningen , Groningen , The Netherlands.
authors.forename: Anna K H
authors.initials: AK
authors.lastname: Hirsch
authors.affiliation: d Molecular Design Group, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin , Ireland , and.|e RCSI Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin , Ireland.
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Moman
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005663:Furans; C000631430:PDK2 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013876:Thiophenes; D019289:Pyruvic Acid; D017346:Protein Serine-Threonine Kinases
keywords: Cancer metabolism; DCA; PDC; PDK2 inhibitors; dichloroacetate; pyruvate