2. Academic Validation
  3. Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors

Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors

  • J Med Chem. 2021 Jan 14;64(1):845-860. doi: 10.1021/acs.jmedchem.0c01835.
Ehesan U Sharif 1,  Jaroslaw Kalisiak 1,  Kenneth V Lawson 1,  Dillon H Miles 1,  Eric Newcomb 1,  Erick A Lindsey 1,  Brandon R Rosen 1,  Laurent P P Debien 1,  Ada Chen 1,  Xiaoning Zhao 1,  Stephen W Young 1,  Nigel P Walker 1,  Norbert Sträter 2,  Emma R Scaletti 2,  Lixia Jin 1,  Guifen Xu 1,  Manmohan R Leleti 1,  Jay P Powers 1
Affiliations

Affiliations

  • 1 Arcus Biosciences, Inc., 3928 Point Eden Way, Hayward, California 94545, United States.
  • 2 Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, D-04103 Leipzig, Germany.
PMID: 33399453 DOI: 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.

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