Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors

Sabin Llona-Minguez*, Andreas Höglund, Artin Ghassemian, Matthieu Desroses, José Manuel Calderón-Montaño, Estefanía Burgos Morón, Nicholas C.K. Valerie, Elisee Wiita, Ingrid Almlöf, Tobias Koolmeister, André Mateus, Cindy Cazares-Körner, Kumar Sanjiv, Evert Homan, Olga Loseva, Pawel Baranczewski, Masoud Darabi, Amir Mehdizadeh, Shabnam Fayezi, Ann Sofie JemthUlrika Warpman Berglund, Kristmundur Sigmundsson, Thomas Lundbäck, Annika Jenmalm Jensen, Per Artursson, Martin Scobie, Thomas Helleday

*Corresponding author for this work
19 Citations (Scopus)

Abstract

The dCTP pyrophosphatase 1 (dCTPase) is a nucleotide pool “housekeeping” enzyme responsible for the catabolism of canonical and noncanonical nucleoside triphosphates (dNTPs) and has been associated with cancer progression and cancer cell stemness. We have identified a series of piperazin-1-ylpyridazines as a new class of potent dCTPase inhibitors. Lead compounds increase dCTPase thermal and protease stability, display outstanding selectivity over related enzymes and synergize with a cytidine analogue against leukemic cells. This new class of dCTPase inhibitors lays the first stone toward the development of drug-like probes for the dCTPase enzyme.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume60
Issue number10
Pages (from-to)4279-4292
Number of pages14
ISSN0022-2623
DOIs
Publication statusPublished - 25.05.2017

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