Discovery of AB680: A Potent and Selective Inhibitor of CD73
| العنوان: | Discovery of AB680: A Potent and Selective Inhibitor of CD73 |
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| المؤلفون: | Brandon Reid Rosen, Manmohan Reddy Leleti, Ada Chen, Sharon Zhao, Jenna L. Jeffrey, Norbert Sträter, Eric T. Newcomb, Jay P. Powers, Kenneth V. Lawson, Lijuan Fu, Dillon H. Miles, Uli Schindler, Wade Berry, Stephen W Young, Tim Park, Emma Scaletti, Lixia Jin, Joanne B.L. Tan, Ehesan U. Sharif, Laurent Debien, Erick Allen Lindsey, Jaroslaw Kalisiak, Susanne Moschütz, Matthew J. Walters, Guifen Xu, Nigel Walker |
| المصدر: | Journal of Medicinal Chemistry. 63:11448-11468 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Models, Molecular, T cell, CD8-Positive T-Lymphocytes, Pharmacology, GPI-Linked Proteins, 01 natural sciences, Small Molecule Libraries, Mice, Structure-Activity Relationship, 03 medical and health sciences, Immune system, Pharmacokinetics, Drug Discovery, medicine, Extracellular, Animals, Humans, Structure–activity relationship, 5'-Nucleotidase, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Binding Sites, Chemistry, Catabolism, Haplorhini, Adenosine, Rats, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, Leukocytes, Mononuclear, Molecular Medicine, Protein Binding, medicine.drug |
| الوصف: | Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human. |
| تدمد: | 1520-4804 0022-2623 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2bb2a8967687083bf528bd8c33e2866fTest https://doi.org/10.1021/acs.jmedchem.0c00525Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....2bb2a8967687083bf528bd8c33e2866f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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