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

被引：34

作者：

Llona-Minguez, Sabin ^{[1
]}

Hoglund, Andreas ^{[1
,8
]}

Jacques, Sylvain A. ^{[1
,9
]}

Johanson, Lars ^{[1
,2
]}

Calderon-Montano, Jose Manuel ^{[1
]}

Claesson, Magnus ^{[4
]}

Loseva, Olga ^{[1
]}

Valerie, Nicholas C. K. ^{[1
]}

Lundback, Thomas ^{[1
,2
]}

Piedrafita, Javier ^{[7
]}

Maga, Giovanni ^{[5
]}

Crespan, Emmanuele ^{[5
]}

Meijer, Laurent ^{[6
]}

Moron, Estefania Burgos ^{[1
]}

Baranczewski, Pawel ^{[1
,3
]}

Hagbjork, Ann-Louise ^{[3
]}

Svensson, Richard ^{[3
]}

Wiita, Elisee ^{[1
]}

Almlof, Ingrid ^{[1
]}

Visnes, Torkild ^{[1
]}

Jeppsson, Fredrik ^{[1
]}

Sigmundsson, Kristmundur ^{[1
,2
,10
]}

Jensen, Annika Jenmalm ^{[1
,2
]}

Artursson, Per ^{[3
]}

Jemth, Ann-Sofie ^{[1
]}

Stenmark, Pal ^{[4
]}

Berglund, Ulrika Warpman ^{[1
]}

Scobie, Martin ^{[1
]}

Helleday, Thomas ^{[1
]}

机构：

[1] Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Div Translat Med & Chem Biol, Stockholm, Sweden

[2] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden, Stockholm, Sweden

[3] Uppsala Univ, Dept Pharm, Sci Life Lab, Uppsala Univ Drug Optimizat & Pharmaceut Profilin, Uppsala, Sweden

[4] Stockholm Univ, Dept Biochem & Biophys, Svante Arrhenius Vag 16C, SE-10691 Stockholm, Sweden

[5] CNR, IGM, Via Abbiategrasso 207, I-27100 Pavia, Italy

[6] ManRos Therapeut, Perharidy Res Ctr, F-29680 Roscoff, Bretagne, France

[7] Torrey Pines Inst Mol Studies, 3550 Gen Atom Court, San Diego, CA 92121 USA

[8] Sprint BioSci AB, Huddinge, Sweden

[9] Univ Strasbourg, Fac Pharm, MEDALIS Drug Discovery Ctr, LFCS,CAMB,UMR7199,CNRS,LIT,UMR7200, F-67401 Illkirch Graffenstaden, France

[10] Duke NUS Grad Med Sch, Singapore, Singapore

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 03期

基金：

欧洲研究理事会; 瑞典研究理事会; 瑞士国家科学基金会;

关键词：

BORONIC ACIDS; PROTEASOME INHIBITOR; DEOXYCYTIDINE; IMPACT; CANCER; ENZYME; CELLS;

D O I：

10.1021/acs.jmedchem.5b01741

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 sternness. 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.

引用

页码：1140 / 1148

页数：9

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