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

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• 作者：Sabin Llona-Minguez ; Andreas H?glund ; Sylvain A. Jacques ; Lars Johansson ; José Manuel Calderón-Monta?o ; Magnus Claesson ; Olga Loseva ; Nicholas C. K. Valerie ; Thomas Lundb?ck ; Javier Piedrafita ; Giovanni Maga ; Emmanuele Crespan ; Laurent Meijer ; Estefanía Burgos Morón ; Pawel Baranczewski ; Ann-Louise Hagbj?rk ; Richard Svensson ; Elisee Wiita ; Ingrid Alml?f ; Torkild Visnes ; Fredrik Jeppsson ; Kristmundur Sigmundsson ; Annika Jenmalm Jensen ; Per Artursson ; Ann-Sofie Jemth ; P?l Stenmark ; Ulrika Warpman Berglund ; Martin Scobie ; Thomas Helleday
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1140-1148
• 全文大小：426K
• ISSN：1520-4804

文摘

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.