title: Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1.
abstract: The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell stemness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sabin
authors.initials: S
authors.lastname: Llona-Minguez
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Höglund
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sylvain A
authors.initials: SA
authors.lastname: Jacques
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Calderón-Montaño
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, SE-106 91 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Claesson
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Loseva
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nicholas C K
authors.initials: NCK
authors.lastname: Valerie
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.affiliation: Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, California 92121, United States.
authors.forename: Javier
authors.initials: J
authors.lastname: Piedrafita
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.affiliation: ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Estefanía Burgos
authors.initials: EB
authors.lastname: Morón
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Pawel
authors.initials: P
authors.lastname: Baranczewski
authors.affiliation: Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Louise
authors.initials: AL
authors.lastname: Hagbjörk
authors.affiliation: Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elisee
authors.initials: E
authors.lastname: Wiita
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Almlöf
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Torkild
authors.initials: T
authors.lastname: Visnes
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jeppsson
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristmundur
authors.initials: K
authors.lastname: Sigmundsson
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika Jenmalm
authors.initials: AJ
authors.lastname: Jensen
authors.affiliation: Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Jemth
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, SE-106 91 Stockholm, Sweden.
authors.forename: Pål
authors.initials: P
authors.lastname: Stenmark
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulrika Warpman
authors.initials: UW
authors.lastname: Berglund
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Scobie
authors.affiliation: Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011755:Pyrophosphatases; C020007:dCTP pyrophosphatase