2. Academic Validation
  3. Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1

Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1

  • J Med Chem. 2017 Mar 9;60(5):2148-2154. doi: 10.1021/acs.jmedchem.6b01786.
Sabin Llona-Minguez 1,  Andreas Höglund 1,  Elisee Wiita 1,  Ingrid Almlöf 1,  André Mateus 2,  José Manuel Calderón-Montaño 1,  Cindy Cazares-Körner 1,  Evert Homan 1,  Olga Loseva 1,  Pawel Baranczewski 1 2,  Ann-Sofie Jemth 1,  Maria Häggblad 3,  Ulf Martens 3,  Bo Lundgren 3,  Per Artursson 2,  Thomas Lundbäck 1 4,  Annika Jenmalm Jensen 1 4,  Ulrika Warpman Berglund 1,  Martin Scobie 1,  Thomas Helleday 1
Affiliations

Affiliations

  • 1 Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
  • 2 Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University , 75123 Uppsala, Sweden.
  • 3 RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University , S-10691 Stockholm, Sweden.
  • 4 Chemical Biology Consortium Sweden, and Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet, 17121 Stockholm, Sweden.
PMID: 28145708 DOI: 10.1021/acs.jmedchem.6b01786
Abstract

The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to Cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit-to-lead development.

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