Articolo in rivista, 2016, ENG, 10.1021/acs.jmedchem.5b01741

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

Llona-Minguez S, Hoglund A, Jacques SA, Johansson L, Calderon-Montano JM, Claesson M, Loseva O, Valerie NC, Lundbäck T, Piedrafita J, Maga G, Crespan E, Meijer L, Burgos Morón E, Baranczewski P, Hagbjork AL, Svensson R, Wiita E, Almlof I, Visnes T, Jeppsson F, Sigmundsson K, Jensen AJ, Artursson P, Jemth AS, Stenmark P, Warpman Berglund U, Scobie M, Helleday T.

Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, Stockholm, SE-106 91, Sweden; Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, Pavia, 27100, Italy; ManRos Therapeutics, Perharidy Research Center, Roscoff, Bretagne, 29680, France; Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA, 92121, United States; Sprint BioScience AB, Huddinge, Sweden; LFCS, CAMB, UMR7199, CNRS, LIT, UMR7200, Université de Strasbourg, MEDALIS Drug Discovery Center, Faculté de Pharmacie, Illkirch, 67401, France; Duke-NUS Graduate Medical School, Singapore

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.

Journal of medicinal chemistry (Online) 59 (3), pp. 1140–1148

Keywords

Inhibitors of Human dCTP Pyrophosphatase 1

CNR authors

Maga Giovanni, Crespan Emmanuele

CNR institutes

IGM – Istituto di genetica molecolare "Luigi Luca Cavalli Sforza"