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J Med Chem. 2017 Mar 9;60(5):2148-2154. doi: 10.1021/acs.jmedchem.6b01786. Epub 2017 Feb 15.

Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1.

Author information

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.

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.

PMID:
28145708
DOI:
10.1021/acs.jmedchem.6b01786
[Indexed for MEDLINE]

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