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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors
Ehesan U Sharif1, Jaroslaw Kalisiak1, Kenneth V Lawson1
1Arcus Biosciences, Inc., 3928 Point Eden Way, Hayward, California 94545, United States.
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.
Insights
Researchers developed novel CD73 inhibitors to combat tumor immune evasion. By blocking CD73, which generates adenosine, these inhibitors aim to restore T-cell and NK-cell functions, offering a promising therapeutic strategy for solid tumors.
Area of Science:
- Biochemistry
- Immunology
- Medicinal Chemistry
Background:
- Solid tumors exhibit high extracellular ATP, leading to adenosine production via ectonucleotidases.
- Adenosine suppresses T-cell and NK-cell functions through adenosine receptors (A2a and A2b).
- CD73, an ectonucleotidase, converts AMP to adenosine, contributing to tumor immune evasion and poor prognosis.
Purpose of the Study:
- To develop potent and selective CD73 inhibitors.
- To explore CD73 inhibition as a strategy to restore anti-tumor immune responses.
- To identify novel therapeutic candidates for solid tumors.
Main Methods:
- Structure-based drug design utilizing known inhibitor AMPCP and hCD73 interactions.
- Structure-activity relationship (SAR) studies to optimize inhibitor properties.
- Development of methylenephosphonic acid-based CD73 inhibitors.
Main Results:
- Discovery of compound 4a, a potent and selective CD73 inhibitor.
- Compound 4a demonstrates exquisite selectivity against related ectonucleotidases.
- Compound 4a exhibits a favorable pharmacokinetic profile.
Conclusions:
- CD73 inhibition is a viable strategy to overcome adenosine-mediated immune suppression in tumors.
- The developed CD73 inhibitors, particularly compound 4a, show therapeutic potential.
- Targeting CD73 can restore anti-tumor immune cell function and improve clinical outcomes.
