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

• Published in: Journal of medicinal chemistry 2017-05, Vol.60 (10), p.4279-4292
• Main Authors: Llona-Minguez, Sabin, Höglund, Andreas, Ghassemian, Artin, Desroses, Matthieu, Calderón-Montaño, José Manuel, Burgos Morón, Estefanía, Valerie, Nicholas C. K, Wiita, Elisee, Almlöf, Ingrid, Koolmeister, Tobias, Mateus, André, Cazares-Körner, Cindy, Sanjiv, Kumar, Homan, Evert, Loseva, Olga, Baranczewski, Pawel, Darabi, Masoud, Mehdizadeh, Amir, Fayezi, Shabnam, Jemth, Ann-Sofie, Warpman Berglund, Ulrika, Sigmundsson, Kristmundur, Lundbäck, Thomas, Jenmalm Jensen, Annika, Artursson, Per, Scobie, Martin, Helleday, Thomas
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biokemi och molekylärbiologi; Biologi (Medicinska tillämpningar under 3 och lantbruksvetenskapliga under 4); Cell Line, Tumor; Cell Survival - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Leukemia - drug therapy; Leukemia - enzymology; Läkemedelskemi; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Medicinska och farmaceutiska grundvetenskaper; Molecular Docking Simulation; Naturvetenskap; Piperazines - chemistry; Piperazines - pharmacology; Pyridazines - chemistry; Pyridazines - pharmacology; Pyrophosphatases - antagonists & inhibitors; Pyrophosphatases - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00182

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.