1. Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors
- Author
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Llona-Minguez, Sabin, Höglund, Andreas, Ghassemian, Artin, Desroses, Matthieu, Calderon-Montano, Jose Manuel, Moron, Estefania Burgos, 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, Berglund, Ulrika Warpman, Sigmundsson, Kristmundur, Lundbäck, Thomas, Jensen, Annika Jenmalm, Artursson, Per, Scobie, Martin, Helleday, Thomas, Llona-Minguez, Sabin, Höglund, Andreas, Ghassemian, Artin, Desroses, Matthieu, Calderon-Montano, Jose Manuel, Moron, Estefania Burgos, 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, Berglund, Ulrika Warpman, Sigmundsson, Kristmundur, Lundbäck, Thomas, Jensen, Annika Jenmalm, Artursson, Per, Scobie, Martin, and Helleday, Thomas
- 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 sternness. 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.
- Published
- 2017
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