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

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Xiaohui Du1, Jared Moore1, Brian R Blank1

  • 1ORIC Pharmaceuticals, 240 E. Grand Avenue, Floor 2, South San Francisco, California 94080, United States.

Journal of Medicinal Chemistry
|September 1, 2020
PubMed

Insights

Novel small molecules targeting CD73, like OP-5244, show promise in cancer immunotherapy. These inhibitors reduce immunosuppressive adenosine (ADO) levels, offering a new strategy against cancer progression.

Area of Science:

  • Biochemistry
  • Immunology
  • Pharmacology

Background:

  • The adenosinergic pathway, particularly CD73-mediated adenosine production, is crucial in cancer immunosuppression.
  • Elevated adenosine levels due to CD73 overexpression correlate with poor prognosis in various cancers.

Purpose of the Study:

  • To design and evaluate novel small-molecule inhibitors of ecto-5-nucleotidase CD73.
  • To assess the therapeutic potential of CD73 inhibition in preclinical cancer models.

Main Methods:

  • Structure-based design of monophosphonate small molecules targeting human CD73.
  • Preclinical evaluation of inhibitor potency, bioavailability, and efficacy in cancer cells, T cells, and mouse models.

Main Results:

  • OP-5244 (compound 35) demonstrated high potency and oral bioavailability as a CD73 inhibitor.
  • OP-5244 completely inhibited adenosine production in cancer cells and CD8+ T cells.
  • In vivo studies showed OP-5244 reversed immunosuppression by modulating the adenosine/AMP ratio.

Conclusions:

  • Small-molecule inhibition of CD73 is a viable strategy for cancer immunotherapy.
  • OP-5244 represents a promising tool compound for further development in treating CD73-dependent cancers.

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