ORIC-533
ORIC-533 is an orally active, highly selective, AMP-competitive CD73 inhibitor that potently blocks adenosine production with sub-nanomolar affinity (Ka=0.03 nM). In multiple myeloma, ORIC-533 restores and enhances the cytotoxicity of the immune system against tumor cells through multiple immunological mechanisms, including reversing the immunosuppressive microenvironment, inducing immunogenic cell death, and activating dendritic cells, T cells and NK cells, with no direct toxicity to normal cells. The combination of ORIC-533 with Daratumumab (HY-P9915) synergistically enhances anti-tumor efficacy, significantly increases intratumoral CD8+ T cell infiltration and inhibits tumor growth in vivo.
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- CAS. Nr.: 2641306-62-7
- Formel: C20H29ClN9O9P
- Molecular Weight:605.93
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
- Reinheit & Dokumentation
- Verweise
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Help & FAQs
Biologische Aktivität
ORIC-533 (0.01-1.0 μM; 3-4 days) exerts dose-dependent killing effects on autologous CD138+ multiple myeloma cells in bone marrow mononuclear cell culture systems derived from patients with relapsed/refractory multiple myeloma, with the maximal activity observed at the concentration of 1.0 μM after 3-4 days of treatment[1].
ORIC-533 (0.01-0.1 μM; 15 min) reduces adenosine production in bone marrow aspirate plasma supernatants from patients with relapsed/refractory multiple myeloma in a dose-dependent manner, with significant inhibitory effects observed at concentrations of 0.01 μM and 0.1 μM after 15 min of incubation[1].
ORIC-533 (0.5 μM; treated for 7-10 days after 2 days of CD3/CD28 stimulation) significantly upregulates the central memory, effector memory, and terminally differentiated effector memory T cell subsets in bone marrow mononuclear cells from multiple myeloma patients following CD3/CD28 stimulation[1].
ORIC-533 (0.5 μM; 3-4 d) induces immunogenic cell death in autologous CD138+ multiple myeloma cells, upregulates cell surface calreticulin (Calreticulin) expression and promotes the extracellular release of high mobility group box 1 (HMGB1) in bone marrow mononuclear cell culture systems derived from patients with multiple myeloma[1].
ORIC-533 (0.5 μM; 24 h) activates plasmacytoid dendritic cells from patients with multiple myeloma, as evidenced by the upregulated expression of activation and maturation markers CD40, CD80, CD83, CD86, and HLA-DR[1].
ORIC-533 (0.5 μM; 2 d) enhances the expression level of CD69 during the activation of CD3+ T cells in the pDC-T cell co-culture system derived from patients with multiple myeloma, which is verified by the increased CD69 expression and the elevated proportion of activated T cells on CD3+ T cells[1].
ORIC-533 (0.5 μM; with bone marrow mononuclear cells for 3 days, co-cultured with U266 cells for 1 day) reduces the viability of HLA-A2+ U266 multiple myeloma cells, and exerts a synergistic effect with daratumumab (HY-P9915)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:U266 cells; Bone marrow mononuclear cells
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Concentration:0.5 μM
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Incubation Time:3 days for bone marrow mononuclear cells, 1 day for U266 cells.
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Result:Reduced the survival rate of allogeneic HLA-A2+ U266 multiple myeloma cells in bone marrow mononuclear cell culture systems from multiple myeloma patients.
Enhanced anti-multiple myeloma (anti-MM) activity when used in combination with Daratumumab (HY-P9915).
| Species | Dose | Route | CL | AUC | Vss | T1/2 | Cmax | F | Tmax |
|---|---|---|---|---|---|---|---|---|---|
| Rat[2] | 0.2 mg/kg | i.v. | 0.079 L/h/kg | 4.21 μM·h | 0.101 L/kg | 1.4 h | / | / | / |
| Rat[2] | 10 mg/kg | p.o. | / | 4.97 μM·h | / | / | 1.45 μM | 2.4 % | / |
| Dog[2] | 0.2 mg/kg | i.v. | 0.071 L/h/kg | 4.90 μM·h | 0.27 L/kg | 3.1 h | / | / | / |
| Dog[2] | 10 mg/kg | p.o. | / | 42.4 μM·h | / | / | 9.37 μM | 17.9 % | 1.3 h |
| Dog[2] | 30 mg/kg | p.o. | / | 143 μM·h | / | / | 35.8 μM | / | 1.0 h |
| Dog[2] | 100 mg/kg | p.o. | / | 239 μM·h | / | / | 57.2 μM | / | 1.3 h |
| Dog[2] | 300 mg/kg | p.o. | / | 643 μM·h | / | / | 159 μM | / | 0.8 h |
| Cynomolgus Monkey[2] | 0.2 mg/kg | i.v. | 0.016 L/h/kg | 21.2 μM·h | 0.0892 L/kg | 4.7 h | / | / | / |
| Cynomolgus Monkey[2] | 10 mg/kg | p.o. | / | 26.5 μM·h | / | / | 3.25 μM | 2.9 % | / |
ORIC-533 (150 mg/kg; p.o.; once daily; for 21 consecutive days) achieves a 67% tumor growth inhibition rate in C57BL/6 mice bearing E.G7-OVA tumors, while increasing the intratumoral level and proliferative capacity of CD8+ T cells[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6 (female)[2]
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Dosage:150 mg/kg
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Administration:p.o.; once daily; 21 consecutive days
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Result:Achieved 67% tumor growth inhibition (TGI) on Day 19.\nIncreased intratumoral CD8+ T-cells to a statistically significant extent compared to vehicle controls.\n
Increased CD8+ proliferation marker Ki67 to a statistically significant extent compared to vehicle controls.\n
Showed no significant differences in mean body weight loss relative to control animals, indicating tolerability.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS. Nr. 2641306-62-7
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Molecular Weight 605.93
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Formel C20H29ClN9O9P
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SMILES
O[C@H]1[C@@H](O)[C@H](N2C3=NC(Cl)=NC(NC4CCCC4)=C3C=N2)O[C@@H]1CO[C@](P(O)(O)=O)(CO)COCC5=NN=NN5
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
[1]. Ray A, et al. A novel small molecule inhibitor of CD73 triggers immune-mediated multiple myeloma cell death. Blood Cancer J. 2024;14(1):58. Published 2024 Apr 9. [Content Brief]
[2]. Moore JT, et al. Discovery of ORIC-533, an Orally Bioavailable CD73 Inhibitor That Maintains Activity in High AMP Environments to Reverse Tumor Immunosuppression. J Med Chem. 2025;68(21):22145-22169. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
ORIC-533 Related Classifications
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