TY - JOUR
T1 - Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors
AU - Llona-Minguez, Sabin
AU - Höglund, Andreas
AU - Ghassemian, Artin
AU - Desroses, Matthieu
AU - Calderón-Montaño, José Manuel
AU - Burgos Morón, Estefanía
AU - Valerie, Nicholas C.K.
AU - Wiita, Elisee
AU - Almlöf, Ingrid
AU - Koolmeister, Tobias
AU - Mateus, André
AU - Cazares-Körner, Cindy
AU - Sanjiv, Kumar
AU - Homan, Evert
AU - Loseva, Olga
AU - Baranczewski, Pawel
AU - Darabi, Masoud
AU - Mehdizadeh, Amir
AU - Fayezi, Shabnam
AU - Jemth, Ann Sofie
AU - Warpman Berglund, Ulrika
AU - Sigmundsson, Kristmundur
AU - Lundbäck, Thomas
AU - Jenmalm Jensen, Annika
AU - Artursson, Per
AU - Scobie, Martin
AU - Helleday, Thomas
N1 - Funding Information:
We acknowledge Dr. Adam Throup and Maghsod Shaaker for insightful manuscript and scientific discussions. This project is primarily supported by The Knut and Alice Wallenberg Foundation. Further support was received from the Felix Mindus Foundation for leukemia research, the Swedish Research Council, the European Research Council, Göran Gustafsson Foundation, Swedish Cancer Society, the Swedish Children’s Cancer Foundation, the Swedish Pain Relief Foundation, and the Torsten and Ragnar Söderberg Foundation. Chemical Biology Consortium Sweden was supported by the Swedish Research Council. We also acknowledge the Faculty of Medicine at Tabriz University of Medical Sciences for providing research facilities and ChemAxon (http://www.chemaxon.com) for technical support. We are grateful to the Protein Science Facility at Karolinska Institutet for purification of proteins.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/5/25
Y1 - 2017/5/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019671552&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b00182
DO - 10.1021/acs.jmedchem.7b00182
M3 - Journal articles
C2 - 28508636
AN - SCOPUS:85019671552
SN - 0022-2623
VL - 60
SP - 4279
EP - 4292
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -