Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production

Du, Xiaohui; Moore, Jared T.; Blank, Brian R.; Eksterowicz, John; Sutimantanapi, Dena; Yuen, Natalie; Metzger, Todd C.; Chan, Brenda; Huang, Tom; Chen, Xi; Chen, Yuping; Duong, Frank; Kong, Wayne; Chang, Jae Hoon; Sun, Jessica; Zavorotinskaya, Tatiana; Ye, Qiuping; Junttila, Melissa R.; Ndubaku, Chudi; Friedman, Lori S.; Fantin, Valeria R.; Sun, Daqing

doi:10.1021/acs.jmedchem.0c01086

Cited by 30 publications

(25 citation statements)

References 45 publications

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“…The initial proof-of-concept preclinical study using an inhibitory antibody against CD73 was performed 11 years ago [96], and at least five different anti-CD73 antibodies (BMS-986179, CPI-006, MEDI9447, NZV930, and TJ004309) and two small-molecule inhibitors (AB122 and LY3475070) are now in Phase I/II clinical trials [95]. Many similar agents are in early-stage discovery and preclinical development [95,[97][98][99][100][101][102]. Somewhat surprisingly, some anti-CD73 antibodies are already being tested for coronavirus disease 2019 (COVID-19) therapy [103,104], despite evidence of clinical benefits of CD73 and adenosine in lung injury [105], and benefit of adenosine in pneumonia associated with COVID-19 [106].…”

Section: Development Of Cd73 Inhibitors and Other Tools To Support Further Researchmentioning

confidence: 99%

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

Alcedo

Bowser

Snider

2021

Trends in Cell Biology

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Purinergic signaling is a fundamental mechanism used by all cells to control their internal activities and interact with the environment. A key component of the purinergic system, the enzyme ecto-5′-nucleotidase (CD73) catalyzes the last step in the extracellular metabolism of ATP to form adenosine. Efforts to harness the therapeutic potential of endogenous adenosine in cancer have culminated in the ongoing clinical development of multiple CD73-targeting antibodies and small-molecule inhibitors. However, recent studies are painting an increasingly complex picture of CD73 mRNA and protein regulation and function in cellular homeostasis, physiological adaptation, and disease development. This review discusses the latest conceptual and methodological advances that are helping to unravel the complexity of this important enzyme that was identified nearly 90 years ago. CD73 is an integral component of the purinergic systemCells produce and consume ATP in a tightly regulated manner to ensure optimal organismal function. In addition to being used as fuel for essential activities within the cell, ATP is also released outside of the cell, where the sequential removal of its phosphate groups results in the formation of the nucleoside adenosine. Extracellular ATP and adenosine, together with associated synthetic and catabolic enzymes, receptors, and transporters, are part of the evolutionarily conserved purinergic system which links cellular metabolism to a myriad of other processes, including proliferation, differentiation, and cell death [1].

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Section: Development Of Cd73 Inhibitors and Other Tools To Support Further Researchmentioning

confidence: 99%

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

Alcedo

Bowser

Snider

2021

Trends in Cell Biology

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“…These uridine-and cytosine-derived α,β-methylene diphosphonates represent an entirely new class of CD73 inhibitors that proved to be potent inhibitors of rat and human CD73 with Ki values in the low nanomolar range, too (Junker et al, 2019). In addition, an orally bioavailable small-molecule CD73 inhibitor (OP-5244) was able to reverse immunosuppression via the blockage of adenosine production (Du et al, 2020). Recent published data has revealed another highly potent (Ki 5 pM) and selective inhibitor of ecto-5′-NT/CD73 (AB680).…”

Section: Ecto-59-nt (Cd73) Inhibitorsmentioning

confidence: 99%

CD39 and CD73 as Promising Therapeutic Targets: What Could Be the Limitations?

et al. 2021

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“…There has been a high level of interest in CD73 as a novel immunotherapy target for cancer, including monoclonal antibodies and small-molecule inhibitors against CD73. 17,[19][20][21][22][23] Small-molecule inhibitors may have advantages versus antibody approaches: for example, the ability of penetration into solid tumor, greater exposure within the TME, and the flexibility of intermittent dosing regarding safety profile, to name a few. Most reports of smallmolecule inhibitors of the enzyme were focused on medicinal chemistry efforts and described structure-activity relationships.…”

Section: Introductionmentioning

confidence: 99%

A Novel CD73 Inhibitor SHR170008 Suppresses Adenosine in Tumor and Enhances Anti-Tumor Activity with PD-1 Blockade in a Mouse Model of Breast Cancer

Liu¹,

Li²,

Liu³

et al. 2021

OTT

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Introduction: CD73 and adenosine support growth-promoting neovascularization, metastasis, and survival in cells, and promote anti-PD-1 mAb therapy-induced immune escape. Consequently, developing a CD73 inhibitor as monotherapy and a potential beneficial combination partner with immune-checkpoint inhibitors needs investigation. Methods: CD73 inhibitors were evaluated in vitro with soluble and membrane-bound CD73 enzymes, as well as its PD biomarker responses in human peripheral blood mononuclear cells (PBMC) by flow cytometry and ELISA. The binding modes of the molecules were analyzed via molecular modeling. The anti-tumor activity and synergistic effect of SHR170008 in combination with anti-PD-1 mAb were evaluated in a syngeneic mouse breast cancer model. Results: SHR170008 was discovered during the initial structural modifications on the link between the ribose and the α-phosphate of AMPCP, which significantly improved the stability of the compound confirmed by the metabolite identification study. Further modifications on the adenine base of AMPCP improved the potency due to forming stronger interactions with CD73 protein. It exhibited potent inhibitory activities on soluble and endogenous membrane-bound CD73 enzymes, and induced IFNγ production, reversed AMPsuppressed CD25 + and CD8 + /CD25 + expression, and enhanced granzyme B production on CD8 + T cells in human PBMC. SHR170008 showed dose-dependent anti-tumor efficacy with suppression of adenosine in the tumors in EMT6 mouse breast tumor model. The increase of adenosine in tumor tissue by anti-PD-1 mAb alone was suppressed by SHR170008 in the combination groups. Simultaneous inhibition of CD73 and PD-1 neutralization synergistically enhanced antitumor immunity and biomarkers in response, and exposures of SHR170008 were correlated with the efficacy readouts. Conclusion:Our findings suggest that CD73 may serve as an immune checkpoint by generating adenosine, which suppresses the antitumor activity of anti-PD-1 mAb, and inhibition of CD73 may be a potential beneficial combination partner with immunecheckpoint inhibitors to improve their therapeutic outcomes in general.

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Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production

Cited by 30 publications

References 45 publications

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

CD39 and CD73 as Promising Therapeutic Targets: What Could Be the Limitations?

A Novel CD73 Inhibitor SHR170008 Suppresses Adenosine in Tumor and Enhances Anti-Tumor Activity with PD-1 Blockade in a Mouse Model of Breast Cancer

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