Oprozomib
Also known as: ONX 0912, Oprozomib, PR-047
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Summary
Oprozomib (ONX‑0912, PR‑047) is an orally bioavailable, irreversible epoxyketone proteasome inhibitor under clinical investigation for the treatment of multiple myeloma and other cancers. As a second‑generation analogue of carfilzomib, it targets the 20S proteasome core, leading to accumulation of ubiquitinated proteins and tumor cell death. Preclinical work highlights anti‑angiogenic activity and synergistic anti‑myeloma effects when combined with dexamethasone and pomalidomide.
Mechanism of Action
Oprozomib binds covalently to the chymotrypsin‑like β5 subunit of the 20S proteasome via its epoxyketone warhead, irreversibly blocking proteolytic activity. This inhibition prevents degradation of poly‑ubiquitinated proteins, causing intracellular protein stress, activation of apoptotic pathways, and disruption of signaling networks that sustain malignant plasma cells. Its oral formulation allows systemic exposure comparable to intravenously administered carfilzomib.
What the Research Shows
Preclinical studies using the chorioallantoic membrane model demonstrated that oprozomib markedly reduces neovascularisation and down‑regulates endothelial markers, indicating anti‑angiogenic potential. In multiple‑myeloma xenograft models (LAGκ‑1A, LAGλ‑1), oprozomib alone suppressed tumor growth, and its combinations with dexamethasone or pomalidomide produced greater tumour regression than any single agent. Triple therapy (oprozomib + pomalidomide + dexamethasone) showed the most pronounced effect across models, supporting ongoing clinical trials. Reviews place oprozomib among emerging proteasome inhibitors being evaluated for relapsed/refractory myeloma and, potentially, solid tumours, though human efficacy data remain limited.
Reported Benefits
Oprozomib offers oral administration, which may improve patient convenience compared with intravenous proteasome inhibitors. Preclinical evidence suggests it can inhibit angiogenesis and enhance anti‑myeloma activity, especially when paired with standard agents such as dexamethasone and pomalidomide. Its irreversible binding may provide sustained proteasome inhibition, potentially translating into effective disease control in relapsed or refractory settings.
Limitations of the Evidence
The compound remains investigational; robust clinical efficacy and safety data are not yet available. Most evidence derives from animal models and early‑phase trials, limiting confidence in its therapeutic advantage over approved agents. Gastro‑intestinal toxicity, a common class effect, has been reported with oral proteasome inhibitors, and the precise mechanisms of such toxicity for oprozomib are still unclear. Long‑term outcomes and optimal combination regimens require further study.
Safety Considerations
Gastro‑intestinal adverse effects—including nausea, vomiting, diarrhoea, and constipation—are frequently observed with proteasome inhibitors and have been noted in studies of oral agents such as oprozomib. Central nervous system toxicities have also been highlighted for the class. Because oprozomib is still in early clinical development, the incidence and severity of these events in patients remain to be fully characterised, and dose‑modification strategies are under investigation.
How It Is Administered
Oprozomib is formulated for oral delivery and taken by mouth. The drug is an irreversible epoxyketone peptide that targets the 20S proteasome after absorption. Specific dosing schedules and formulations are defined in clinical trial protocols and are not yet part of standard medical practice.
Routes of Administration
Goals & Uses
- Mantle Cell LymphomaOncologyLow
- Multiple MyelomaOncologyModerate
- Proteasome inhibitor resistance circumventionOncologyLow
- Multiple myeloma treatmentOncologyModerate
- Non-Hodgkin lymphoma treatmentOncologyLow
- Waldenström's macroglobulinemia treatmentOncologyLow
Contraindications
- Severe hepatic impairment (Child‑Pugh C)Liver DiseaseModerate
- Severe hepatic impairmentOrganHighLiver function concerns
- PregnancyPopulationHighPotential fetal risk or insufficient safety data
- Hypersensitivity to oprozomib or related epoxyketone inhibitorsAllergyHigh
- Known hypersensitivity to oprozomib or excipientsAllergyHigh
Adverse Effects
- Peripheral neuropathyNeurologicalUncommon
- ThrombocytopeniaHematologicCommonLow platelet count
- Gastrointestinal toxicity (nausea, vomiting, diarrhea)GastrointestinalCommon
- AnemiaHematologicCommonLow red blood cell count or hemoglobin
- NeutropeniaHematologicCommonLow neutrophil count
- NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
- FatigueGeneralCommonLow energy or tiredness
- Cardiac adverse eventsCardiovascularUncommon
- DiarrheaGastrointestinalCommonLoose or frequent stools
Drug Interactions
- Anticoagulants (e.g., warfarin)Moderate
- CYP3A4 inducers (e.g., rifampin)Moderate
- CYP3A4 inducers (e.g., rifampin, carbamazepine)Moderate
- CYP3A4 inhibitors (e.g., ketoconazole)Moderate
- DexamethasoneLow
- CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)Moderate
Population Constraints
- PregnancyReproductive SafetyAbsolute
- Severe renal impairmentOrgan ImpairmentRelative
- Pediatric patientsAgeRelative
- Pregnant or breastfeeding womenReproductiveRelative
- Patients with pre-existing cardiac diseaseCardiovascularRelative
Regulatory Status
- European UnionInvestigationalUnder clinical evaluation
- United StatesInvestigationalPhase I/II trials ongoing
- United KingdomInvestigationalNo marketing authorisation
Not approved in any jurisdiction; ongoing Phase I/II trials as of 2024.
Evidence & Sources
- Journal ArticleModerateStansborough RL, Gibson RJ2017-01-01T00:00:00.000000Z
- Journal ArticleModerateGazzaroli G, et al.2023-01-01T00:00:00.000000Z
- Journal ArticleModerateEl-Amm J, Tabbara IA2015-01-01T00:00:00.000000Z
- Journal ArticleModerateSanchez E, et al.2017-01-01T00:00:00.000000Z
- Journal ArticleModerateYang Y, et al.2020-01-01T00:00:00.000000Z
- Journal ArticleModerateDeng L, et al.2020-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of cancer is oprozomib being studied for?
The primary focus of clinical investigation is multiple myeloma, particularly in relapsed or refractory disease. Preclinical work also explores its potential against solid tumours, but human trials have not yet expanded beyond hematologic malignancies.
How does oprozomib differ from carfilzomib?
Oprozomib is an oral analogue of carfilzomib that retains the irreversible epoxyketone mechanism but is designed for convenient oral dosing rather than intravenous infusion. This may affect pharmacokinetics and side‑effect profiles.
Are there any known side effects?
Gastro‑intestinal disturbances such as nausea, vomiting, diarrhoea, and constipation have been reported with oral proteasome inhibitors, including oprozomib. Central nervous system effects have also been observed with the drug class, though specific rates for oprozomib are still being defined.
Can oprozomib be used alone or must it be combined with other drugs?
Preclinical data show anti‑myeloma activity both as monotherapy and in combination. Combination with dexamethasone and pomalidomide produced the strongest tumour suppression in animal models, suggesting that multi‑drug regimens may be optimal in future clinical use.
Is oprozomib approved for clinical use?
No. Oprozomib remains an investigational agent in clinical trials and has not received regulatory approval for any indication.
What is Oprozomib?
Oprozomib (ONX‑0912, PR‑047) is an orally bioavailable, irreversible epoxyketone proteasome inhibitor under clinical investigation for the treatment of multiple myeloma and other cancers. As a second‑generation analogue of carfilzomib, it targets the 20S proteasome core, leading to accumulation of ubiquitinated proteins and tumor cell death. Preclinical work highlights anti‑angiogenic activity and synergistic anti‑myeloma effects when combined with dexamethasone and pomalidomide.
What is Oprozomib used for?
Oprozomib is educationally associated with: Mantle Cell Lymphoma, Multiple Myeloma, Proteasome inhibitor resistance circumvention, Multiple myeloma treatment, Non-Hodgkin lymphoma treatment, Waldenström's macroglobulinemia treatment. Educational only — not medical advice.
How is Oprozomib administered?
Recorded routes of administration: Oral.
What are the potential side effects of Oprozomib?
Reported adverse effects include: Peripheral neuropathy, Thrombocytopenia, Gastrointestinal toxicity (nausea, vomiting, diarrhea), Anemia, Neutropenia, Nausea, Fatigue, Cardiac adverse events, Diarrhea. This list is not exhaustive — consult a qualified clinician.
Who should avoid Oprozomib?
Recorded contraindications: Severe hepatic impairment (Child‑Pugh C), Severe hepatic impairment, Pregnancy, Hypersensitivity to oprozomib or related epoxyketone inhibitors, Known hypersensitivity to oprozomib or excipients. Consult a qualified clinician before use.