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 Jemth; Ulrika Warpman Berglund; Kristmundur Sigmundsson; Thomas Lundbäck; Annika Jenmalm Jensen; Per Artursson; Martin Scobie; Thomas Helleday

doi:10.1021/acs.jmedchem.7b00182

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

Clinic of Hematology and Oncology

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 language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	10
Pages (from-to)	4279-4292
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00182
Publication status	Published - 25.05.2017

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Llona-Minguez, S., Höglund, A., Ghassemian, A., Desroses, M., Calderón-Montaño, J. M., Burgos Morón, E., Valerie, N. C. K., 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., ... Helleday, T. (2017). Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors. Journal of Medicinal Chemistry, 60(10), 4279-4292. https://doi.org/10.1021/acs.jmedchem.7b00182

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title = "Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors",

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.",

author = "Sabin Llona-Minguez and Andreas H{\"o}glund and Artin Ghassemian and Matthieu Desroses and Calder{\'o}n-Monta{\~n}o, {Jos{\'e} Manuel} and {Burgos Mor{\'o}n}, Estefan{\'i}a and Valerie, {Nicholas C.K.} and Elisee Wiita and Ingrid Alml{\"o}f and Tobias Koolmeister and Andr{\'e} Mateus and Cindy Cazares-K{\"o}rner and Kumar Sanjiv and Evert Homan and Olga Loseva and Pawel Baranczewski and Masoud Darabi and Amir Mehdizadeh and Shabnam Fayezi and Jemth, {Ann Sofie} and {Warpman Berglund}, Ulrika and Kristmundur Sigmundsson and Thomas Lundb{\"a}ck and {Jenmalm Jensen}, Annika and Per Artursson and Martin Scobie and Thomas Helleday",

note = "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, G{\"o}ran Gustafsson Foundation, Swedish Cancer Society, the Swedish Children{\textquoteright}s Cancer Foundation, the Swedish Pain Relief Foundation, and the Torsten and Ragnar S{\"o}derberg 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: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

month = may,

day = "25",

doi = "10.1021/acs.jmedchem.7b00182",

language = "English",

volume = "60",

pages = "4279--4292",

journal = "Journal of Medicinal Chemistry",

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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 2017, 'Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors', Journal of Medicinal Chemistry, vol. 60, no. 10, pp. 4279-4292. https://doi.org/10.1021/acs.jmedchem.7b00182

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.

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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 -

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

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