Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors
Autor: | Dillon H. Miles, Nigel Walker, Manmohan Reddy Leleti, Xiaoning Zhao, Eric T. Newcomb, Kenneth V. Lawson, Jaroslaw Kalisiak, Erick Allen Lindsey, Lixia Jin, Ada Chen, Laurent Debien, Guifen Xu, Ehesan U. Sharif, Norbert Sträter, Brandon Reid Rosen, Stephen W Young, Emma Scaletti, Jay P. Powers |
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Rok vydání: | 2021 |
Předmět: |
Adenosine
Phosphorous Acids Drug Evaluation Preclinical Molecular Dynamics Simulation Crystallography X-Ray GPI-Linked Proteins 01 natural sciences Structure-Activity Relationship 03 medical and health sciences Immune system ATP hydrolysis Drug Discovery medicine Extracellular Humans Ectonucleotidase 5'-Nucleotidase 030304 developmental biology chemistry.chemical_classification 0303 health sciences Tumor microenvironment Binding Sites Adenosine receptor 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme chemistry Biochemistry Drug Design Molecular Medicine medicine.drug |
Zdroj: | Journal of Medicinal Chemistry. 64:845-860 |
ISSN: | 1520-4804 0022-2623 |
Popis: | 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. |
Databáze: | OpenAIRE |
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