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American Chemical Society, Journal of Medicinal Chemistry, 3(59), p. 1140-1148, 2016

DOI: 10.1021/acs.jmedchem.5b01741

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Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1

Journal article published in 2016 by Sabin Llona-Minguez, Andreas Höglund, Sylvain A. Jacques, Lars Johansson, José Manuel Calderón-Montaño, Magnus Claesson, Olga Loseva, Nicholas C. K. Valerie ORCID, Thomas Lundbäck, Javier Piedrafita, Giovanni Maga, Emmanuele Crespan, Laurent Meijer, Estefanía Burgos Morón, Pawel Baranczewski and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Abstract

The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and non-canonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell stemness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.