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Discovery of ORIC-533, an Orally Bioavailable CD73 Inhibitor That Maintains Activity in High AMP Environments to
Jared T Moore1, Hiroyuki Kawai1, Brian R Blank1
1ORIC Pharmaceuticals, Inc., 240 East Grand Avenue, Fl2, South San Francisco, California 94080, United States.
Abstract:
Immunosuppressive adenosine (ADO) is catabolized from adenosine monophosphate (AMP) by CD73 in the tumor microenvironment and corresponds to poor patient prognosis in many cancers. Reducing levels of ADO via inhibition of CD73 may reverse this immunosuppression. Herein we describe the discovery of ORIC-533 (6), an inhibitor of CD73 with subnanomolar biochemical potency and potent cellular activity in both human and mouse tumor cell lines. Compound 6 rescues T-cell activation and cytokine production at low nanomolar concentrations, showing robust immunomodulatory activity. Notably, in high AMP environments compound 6 also promotes CD8+ T-cell proliferation. Oral dosing of 6 reduces the concentration of ADO in the tumor microenvironment with a concomitant increase in CD8+ cells, resulting in tumor growth inhibition in a syngeneic mouse model of cancer. The strong potency and oral bioavailability support a potential best-in-class profile for 6, a CD73 inhibitor that entered phase 1b in patients with multiple myeloma.
Insights
CD73 inhibition reduces immunosuppressive adenosine in tumors, enhancing T-cell activity. ORIC-533, a potent CD73 inhibitor, demonstrated tumor growth inhibition in preclinical models and is now in clinical trials.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Tumor microenvironment immunosuppression by adenosine (ADO), produced by CD73 from AMP, correlates with poor cancer prognosis.
- Targeting CD73 to reduce ADO levels offers a strategy to reverse tumor immunosuppression.
Purpose of the Study:
- To discover and characterize novel CD73 inhibitors for cancer immunotherapy.
- To evaluate the preclinical efficacy of ORIC-533, a potent CD73 inhibitor.
Main Methods:
- Biochemical and cellular assays to determine the potency of ORIC-533 against CD73.
- In vitro assessment of immunomodulatory effects on T-cells and cytokine production.
- In vivo studies using a syngeneic mouse cancer model to evaluate tumor growth inhibition and pharmacodynamic effects.
Main Results:
- ORIC-533 demonstrated subnanomolar biochemical potency and potent cellular activity against CD73 in human and mouse cell lines.
- Compound 6 effectively rescued T-cell activation and cytokine production at nanomolar concentrations.
- Oral administration of ORIC-533 reduced tumor ADO levels, increased CD8+ T-cells, and inhibited tumor growth in vivo.
Conclusions:
- ORIC-533 is a potent, orally bioavailable CD73 inhibitor with significant immunomodulatory and anti-tumor activity.
- These findings support the potential of ORIC-533 as a best-in-class therapeutic for cancer, including multiple myeloma.
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