Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73

被引：49

作者：

Beatty, Joel W. ^{[1
]}

Lindsey, Erick A. ^{[1
]}

Thomas-Tran, Rhiannon ^{[1
]}

Debien, Laurent ^{[1
]}

Mandal, Debashis ^{[1
]}

Jeffrey, Jenna L. ^{[1
]}

Tran, Anh T. ^{[1
]}

Fournier, Jeremy ^{[1
]}

Jacob, Steven D. ^{[1
]}

Yan, Xuelei ^{[1
]}

Drew, Samuel L. ^{[1
]}

Ginn, Elaine ^{[1
]}

Chen, Ada ^{[1
]}

Pham, Amber T. ^{[1
]}

Zhao, Sharon ^{[1
]}

Jin, Lixia ^{[1
]}

Young, Stephen W. ^{[1
]}

Walker, Nigel P. ^{[1
]}

Leleti, Manmohan Reddy ^{[1
]}

Moschuetz, Susanne ^{[2
]}

Straeter, Norbert ^{[2
]}

Powers, Jay P. ^{[1
]}

Lawson, Kenneth, V ^{[1
]}

机构：

[1] Arcus Biosci Inc, Hayward, CA 94545 USA

[2] Univ Leipzig, Ctr Biotechnol & Biomed, Inst Bioanalyt Chem, D-04103 Leipzig, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 08期

关键词：

ECTO-5'-NUCLEOTIDASE; INSIGHTS; 5-NUCLEOTIDASE; EXPRESSION; ANTI-CD73; ADENOSINE; THERAPY; CD39;

D O I：

10.1021/acs.jmedchem.9b01713

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4(-{5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5[4-4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.

引用

页码：3935 / 3955

页数：21

共 32 条

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