Discovery of ORIC-533, an Orally Bioavailable CD73 Inhibitor That Maintains Activity in High AMP Environments to Reverse Tumor Immunosuppression

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.