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 (<b>6</b>), an inhibitor of CD73 with subnanomolar biochemical potency and potent cellular activity in both human and mouse tumor cell lines. Compound <b>6</b> rescues T-cell activation and cytokine production at low nanomolar concentrations, showing robust immunomodulatory activity. Notably, in high AMP environments compound <b>6</b> also promotes CD8<sup>+</sup> T-cell proliferation. Oral dosing of <b>6</b> reduces the concentration of ADO in the tumor microenvironment with a concomitant increase in CD8<sup>+</sup> 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 <b>6</b>, a CD73 inhibitor that entered phase 1b in patients with multiple myeloma.
Authors
- Chien‐Hung Yeh (ORCID: https://orcid.org/0000-0002-8320-1486)
- Chudi Ndubaku (ORCID: https://orcid.org/0000-0003-4183-0417)
- Sumeet Salaniwal (ORCID: https://orcid.org/0009-0002-4744-5317)
- Jae Hoon Chang (ORCID: https://orcid.org/0000-0003-3457-7695)
- Tatiana Zavorotinskaya
- Daqing Sun (ORCID: https://orcid.org/0000-0001-9578-8790)
- Natalie Yuen
- Brian R. Blank (ORCID: https://orcid.org/0009-0003-4763-9856)
- Melissa R. Junttila (ORCID: https://orcid.org/0000-0003-3538-1192)
- Dena Sutimantanapi
- Todd C. Metzger (ORCID: https://orcid.org/0000-0002-5709-8876)
- Mohammad H. Al‐Sayah (ORCID: https://orcid.org/0000-0001-6321-0556)
- Robert Warne (ORCID: https://orcid.org/0009-0009-2738-3121)
- Jared T. Moore (ORCID: https://orcid.org/0000-0001-8197-7208)
- John Eksterowicz
- Yosup Rew (ORCID: https://orcid.org/0000-0003-1155-4298)
- Frank Duong
- Valeria R. Fantin (ORCID: https://orcid.org/0009-0005-8328-0152)
- Ke‐Jia Wu (ORCID: https://orcid.org/0000-0002-0809-5628)
- Wayne Kong
- Erica L. Jackson (ORCID: https://orcid.org/0000-0002-7100-8021)
- Xi Chen (ORCID: https://orcid.org/0000-0002-7995-6202)
- Yuping Chen (ORCID: https://orcid.org/0009-0000-0101-9713)
- Xiaohui Du (ORCID: https://orcid.org/0000-0001-5444-9434)
- Hiroyuki Kawai (ORCID: https://orcid.org/0000-0002-4298-4373)
- Lori S. Friedman (ORCID: https://orcid.org/0000-0001-9127-9892)
- Brenda Chan
- Jessica D. Sun (ORCID: https://orcid.org/0000-0002-9844-9767)
- Johnny D. Pham
- Qilu Ye
- Liusheng Zhu
Institutions
- Sunesis (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02153
- Citations
- 1
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.12