Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73
| العنوان: | Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73 |
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| المؤلفون: | Stephen W Young, Debashis Mandal, Sharon Zhao, Susanne Moschütz, Ada Chen, Elaine Ginn, Lixia Jin, Samuel L Drew, Nigel Walker, Erick Allen Lindsey, Jay P. Powers, Kenneth V. Lawson, Xuelei Yan, Anh Tran, Rhiannon Thomas-Tran, Amber Pham, Manmohan Reddy Leleti, Jenna L. Jeffrey, Steven D. Jacob, Norbert Sträter, Joel W. Beatty, Jeremy Fournier, Laurent Debien |
| المصدر: | Journal of Medicinal Chemistry. 63:3935-3955 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Membrane permeability, Stereochemistry, CHO Cells, Crystallography, X-Ray, GPI-Linked Proteins, Binding, Competitive, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, Cricetinae, Drug Discovery, medicine, Animals, Humans, Nucleotide, 5'-Nucleotidase, Cells, Cultured, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Chemistry, Triazoles, Purinergic signalling, Adenosine, Small molecule, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Benzonitrile, Enzyme, Hepatocytes, Molecular Medicine, Nucleoside, medicine.drug |
| الوصف: | 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-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. |
| تدمد: | 1520-4804 0022-2623 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1cb1d479ddd330a628c6dc7fec984840Test https://doi.org/10.1021/acs.jmedchem.9b01713Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....1cb1d479ddd330a628c6dc7fec984840 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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