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

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Llona-Minguez S, Höglund A, Ghassemian A, Desroses M, Calderón-Montaño JM, Burgos Morón E, Valerie NCK, Wiita E, Almlöf I, Koolmeister T, Mateus A, Cazares-Körner C, Sanjiv K, Homan E, Loseva O, Baranczewski P, Darabi M, Mehdizadeh A, Fayezi S, Jemth AS, Warpman Berglund U, Sigmundsson K, Lundbäck T, Jenmalm Jensen A, Artursson P, Scobie M, Helleday T

J. Med. Chem. 60 (10) 4279-4292 [2017-05-25; online 2017-05-16]

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.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

Drug Discovery and Development (DDD) [Collaborative]

Protein Science Facility (PSF) [Service]

PubMed 28508636

DOI 10.1021/acs.jmedchem.7b00182

Crossref 10.1021/acs.jmedchem.7b00182