Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1
Sabin Llona‐Minguez(Science for Life Laboratory), Andreas Höglund(Karolinska Institutet), Sylvain A. Jacques(Science for Life Laboratory), Lars Johansson(Science for Life Laboratory), José Manuel Calderón‐Montaño(Science for Life Laboratory), Magnus Claesson(Stockholm University), Olga Loseva(Science for Life Laboratory), Nicholas C.K. Valerie(Science for Life Laboratory), Thomas Lundbäck(Science for Life Laboratory), Javier Piedrafita(General Atomics (United States)), Giovanni Maga(Istituto di Genetica Molecolare), Emmanuele Crespan(Istituto di Genetica Molecolare), Laurent Meijer(ManRos Therapeutics (France)), Estefanía Burgos‐Morón(Karolinska Institutet), Paweł Baranczewski(Karolinska Institutet), Ann-Louise Hagbjörk(Uppsala University), Richard Svensson(Uppsala University), Elisée Wiita(Science for Life Laboratory), Ingrid Almlöf(Science for Life Laboratory), Torkild Visnes(Science for Life Laboratory), Fredrik Jeppsson(Karolinska Institutet), Kristmundur Sigmundsson(Science for Life Laboratory), Annika Jenmalm Jensen(Karolinska Institutet), Per Artursson(Uppsala University), Ann‐Sofie Jemth(Karolinska Institutet), Pål Stenmark(Stockholm University), Ulrika Warpman Berglund(Science for Life Laboratory), Martin Scobie(Science for Life Laboratory), Thomas Helleday(Science for Life Laboratory)
Cited by 48Open Access
Abstract
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.
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