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
  • 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.

Products