2. Academic Validation
  3. Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1

Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1

  • J Med Chem. 2016 Feb 11;59(3):1140-1148. doi: 10.1021/acs.jmedchem.5b01741.
Sabin Llona-Minguez  # 1,  Andreas Höglund  # 1,  Sylvain A Jacques 1,  Lars Johansson 1 2,  José Manuel Calderón-Montaño 1,  Magnus Claesson 3,  Olga Loseva 1,  Nicholas C K Valerie 1,  Thomas Lundbäck 1 2,  Javier Piedrafita 4,  Giovanni Maga 5,  Emmanuele Crespan 5,  Laurent Meijer 6,  Estefanía Burgos Morón 1,  Pawel Baranczewski 1 7,  Ann-Louise Hagbjörk 7,  Richard Svensson 7,  Elisee Wiita 1,  Ingrid Almlöf 1,  Torkild Visnes 1,  Fredrik Jeppsson 1,  Kristmundur Sigmundsson 1 2,  Annika Jenmalm Jensen 1 2,  Per Artursson 7,  Ann-Sofie Jemth 1,  Pål Stenmark 3,  Ulrika Warpman Berglund 1,  Martin Scobie 1,  Thomas Helleday 1
Affiliations

Affiliations

  • 1 Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • 2 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.
  • 3 Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, SE-106 91 Stockholm, Sweden.
  • 4 Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, California 92121, United States.
  • 5 Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
  • 6 ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
  • 7 Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • # Contributed equally.
PMID: 26771665 DOI: 10.1021/acs.jmedchem.5b01741
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.

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