9R0G

Human CD73 (ecto 5'-nucleotidase) in complex with compound 21

This is a non-PDB format compatible entry.

Summary for 9R0G

• Entry DOI: 10.2210/pdb9r0g/pdb
• Descriptor: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: 5'-nucleotidase, hydrolase, phosphatase, inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 120952.86

Authors

Moore, J.T.,Ivic, N.,Lammens, A.,Krapp, S.,Maskos, K. (deposition date: 2025-04-24, release date: 2025-11-12, Last modification date: 2025-11-26)

Primary citation

Moore, J.T.,Kawai, H.,Blank, B.R.,Wu, K.,Yeh, C.H.,Zhu, L.,Pham, J.D.,Rew, Y.,Eksterowicz, J.,Salaniwal, S.,Sutimantanapi, D.,Warne, R.,Yuen, N.,Metzger, T.C.,Chan, B.,Huang, T.,Chen, X.,Chen, Y.,Duong, F.,Kong, W.,Chang, J.H.,Sun, J.D.,Zavorotinskaya, T.,Ye, Q.,Al-Sayah, M.A.,Jackson, E.,Junttila, M.R.,Fantin, V.R.,Ndubaku, C.O.,Sun, D.,Du, X.,Friedman, L.S.
Discovery of ORIC-533, an Orally Bioavailable CD73 Inhibitor That Maintains Activity in High AMP Environments to Reverse Tumor Immunosuppression.
J.Med.Chem., 68:22145-22169, 2025

PubMed 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 (), an inhibitor of CD73 with subnanomolar biochemical potency and potent cellular activity in both human and mouse tumor cell lines. Compound rescues T-cell activation and cytokine production at low nanomolar concentrations, showing robust immunomodulatory activity. Notably, in high AMP environments compound also promotes CD8 T-cell proliferation. Oral dosing of 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 , a CD73 inhibitor that entered phase 1b in patients with multiple myeloma.

PubMed: 41139398
DOI: 10.1021/acs.jmedchem.5c02153

Experimental method

X-RAY DIFFRACTION (2.43 Å)