Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors
- 5 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (1), 845-860
- https://doi.org/10.1021/acs.jmedchem.0c01835
Abstract
Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5′-(α,β-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure–activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.Keywords
This publication has 20 references indexed in Scilit:
- α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) InhibitorsJournal of Medicinal Chemistry, 2015
- Prodrugs of Phosphonates and Phosphates: Crossing the Membrane BarrierPublished by Springer Science and Business Media LLC ,2014
- CD39 and CD73 in immunity and inflammationTrends in Molecular Medicine, 2013
- Crystal Structure of the Human Ecto-5′-Nucleotidase (CD73): Insights into the Regulation of Purinergic SignalingStructure, 2012
- Ectonucleotidases in Tumor Cells and Tumor-Associated Immune Cells: An OverviewJournal of Biomedicine and Biotechnology, 2012
- Anti-CD73 antibody therapy inhibits breast tumor growth and metastasisProceedings of the National Academy of Sciences of the United States of America, 2010
- Ecto-5’-nucleotidase: Structure function relationshipsPurinergic Signalling, 2006
- Synthesis of 6-Amino-, 6-Methyl- and 6-Aryl-2-(hydroxymethyl)purine Bases and NucleosidesCollection of Czechoslovak Chemical Communications, 2006
- 5′-Nucleotidase: molecular structure and functional aspectsBiochemical Journal, 1992
- Preparation of 5'-O-phosphonylmethyl analogues of nucleoside-5'-phosphates, 5'-diphosphates and 5'-triphosphatesCollection of Czechoslovak Chemical Communications, 1982