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

Llona-Minguez S, Höglund A, Jacques SA, Johansson L, Calderón-Montaño JM, Claesson M, Loseva O, Valerie NCK, Lundbäck T, Piedrafita J, Maga G, Crespan E, Meijer L, Morón EB, Baranczewski P, Hagbjörk AL, Svensson R, Wiita E, Almlöf I, Visnes T, Jeppsson F, Sigmundsson K, Jensen AJ, Artursson P, Jemth AS, Stenmark P, Berglund UW, Scobie M, Helleday T

J. Med. Chem. 59 (3) 1140-1148 [2016-02-11; online 2016-01-27]

The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical 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.

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

Drug Discovery and Development (DDD) [Collaborative]

Protein Science Facility (PSF) [Service]

PubMed 26771665

DOI 10.1021/acs.jmedchem.5b01741

Crossref 10.1021/acs.jmedchem.5b01741

pmc: PMC4753678
mid: EMS66984

Laboratories for Chemical Biology at Karolinska Institutet (LCBKI)
Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)