- |||||||||| oprozomib (ONX 0912) / Amgen
Preclinical, Journal: Tissue-, region-, and gene-specific induction of microsomal epoxide hydrolase expression and activity in the mouse intestine by arsenic in drinking water. (Pubmed Central) - Jun 17, 2024
The induction of intestinal mEH was accompanied by increases in microsomal enzymatic activities toward a model mEH substrate, cis-stilbene oxide, and an epoxide-containing drug, oprozomib, in vitro, and by increases in the levels of PR-176, the main hydrolysis metabolite of oprozomib, in the proximal small intestine of oprozomib-treated mice...The small intestinal epithelial cells are the main site of absorption of ingested arsenic, but they are not well characterized for arsenic exposure-related changes. This study identified gene expression changes in the small intestine that may be mechanistically linked to the adverse effects of arsenic exposure and possible interactions between arsenic ingestion and the pharmacokinetics of epoxide-containing drugs in vivo.
- |||||||||| Journal: Potential mechanisms and drug prediction of Rheumatoid Arthritis and primary Sj (Pubmed Central) - Feb 19, 2024
In conclusion, we identified commom targets as potential biomarkers in RA and pSS from publicly available databases and predicted potential drugs based on the targets. A new understanding of the molecular mechanisms associated with RA and pSS is provided according to the miRNA-gene network.
- |||||||||| oprozomib (ONX 0912) / Amgen, marizomib (NPI-0052) / Triphase Accelerator Corporation, BMS, Ninlaro (ixazomib) / Takeda
Review, Journal: Proteasome inhibitors as anticancer agents. (Pubmed Central) - Jan 15, 2024
The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood-brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic 'working on' aspect for the near future.
- |||||||||| Review, Journal: Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials? (Pubmed Central) - May 12, 2023
We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival.
- |||||||||| PK/PD data, Journal: Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia. (Pubmed Central) - Mar 27, 2023
However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival. Once validated, it is proposed that a combination of selected drugs can be evaluated in the laboratory to treat WM.
- |||||||||| oprozomib (ONX 0912) / Amgen
Journal: Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner. (Pubmed Central) - Jan 8, 2022
Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition.
- |||||||||| oprozomib (ONX 0912) / Amgen
Trial completion date, Trial primary completion date, Combination therapy: INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - Dec 23, 2021
P1b, N=61, Active, not recruiting,
Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition. Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022
- |||||||||| Review, Journal: The role of ubiquitination in tumorigenesis and targeted drug discovery. (Pubmed Central) - Oct 9, 2021
In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.
- |||||||||| Journal: Research progress in proteasome inhibitor resistance to multiple myeloma. (Pubmed Central) - Sep 28, 2021
However, the drug resistance of PIs in MM is still a problem. The mechanisms for PIs resistance to MM include ubiquitin-proteasome pathway, autophagy lysosome pathway, endoplasmic reticulum stress pathway, cell survival signal pathway, exosome-mediated resistance, and bone marrow microenvironment-mediated resistance.
- |||||||||| Review, Journal: Emerging agents and regimens for multiple myeloma. (Pubmed Central) - Jun 8, 2021
BCMA-targeted BiTE, antibody-drug conjugates and CAR-T cells have the potential to revolutionize the therapy for RRMM. In this review, we summarized the latest clinical development of these novel agents and regimens.
- |||||||||| delanzomib (CEP-18770) / Teva, oprozomib (ONX 0912) / Amgen, Ninlaro (ixazomib) / Takeda
Journal: Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions. (Pubmed Central) - Mar 7, 2021
The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delanzomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug-drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.
- |||||||||| oprozomib (ONX 0912) / Amgen
Trial termination, Combination therapy: Oprozomib and Dexamethasone,in Combination With Lenalidomide or Oral Cyclophosphamide to Treat Newly Diagnosed Multiple Myeloma (clinicaltrials.gov) - Mar 3, 2021
P1b/2, N=22, Terminated,
Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delanzomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug-drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs. Completed --> Terminated; A program evaluation identified that the safety profile and pharmacokinetic (PK) characteristics of the formulation used in all oprozomib studies required further optimization and thus enrollment in OPZ003 was halted during dose-escalation.
- |||||||||| oprozomib (ONX 0912) / Amgen
Trial termination: Open-label Study of the Safety and Activity of Oprozomib in Patients With Hematologic Malignancies (clinicaltrials.gov) - Feb 21, 2021
P1b/2, N=210, Terminated,
Conclusively, this study demonstrated that prolonged inhibition of proteasome to trigger UPR could be an alternative strategy for treating CML in the light of TKIs resistance. Completed --> Terminated; A program evaluation identified that the safety profile and pharmacokinetic (PK) characteristics of the formulation used in all oprozomib studies required further optimization and thus enrollment in 2011-001 was halted.
- |||||||||| oprozomib (ONX 0912) / Amgen
Trial termination, Metastases: A Phase 1 Study of Oprozomib to Assess Food Effect, Drug-Drug Interaction With Midazolam, and Safety and Tolerability in Patients With Advanced Malignancies (clinicaltrials.gov) - Feb 21, 2021
P1, N=43, Terminated,
Completed --> Terminated; A program evaluation identified that the safety profile and pharmacokinetic (PK) characteristics of the formulation used in all oprozomib studies required further optimization and thus enrollment in 2011-001 was halted. Completed --> Terminated; Why study stopped revised to "A program evaluation identified that the safety profile and pharmacokinetic (PK) characteristics of the formulation used in all oprozomib studies required further optimization and thus enrollment in OPZ009 was halted
- |||||||||| oprozomib (ONX 0912) / Amgen
Journal: The active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms. (Pubmed Central) - Jan 23, 2021
This preclinical study reveals the involvement of the proteasome in the oxaliplatin-induced neuropathy and adds useful information to better understand the molecular mechanism underlying this pain condition. Moreover, although further evidence is required, these findings suggest that oprozomib could be a therapeutic option to counteract chemotherapy-induced neuropathy.
- |||||||||| oprozomib (ONX 0912) / Amgen
Trial completion date, Trial primary completion date, Combination therapy: INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - Dec 8, 2020
P1b, N=61, Active, not recruiting,
Moreover, although further evidence is required, these findings suggest that oprozomib could be a therapeutic option to counteract chemotherapy-induced neuropathy. Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021
- |||||||||| Journal: Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. (Pubmed Central) - Nov 19, 2020
In addition, the mechanism of action of the immunoproteasome inhibitors, ONX-0914 and LU-102, suggested their therapeutic role in the combination treatment with PIs. In the current review, we discuss various PIs and their underlying mechanisms in surmounting anti-tumor drug resistance when used in combination with conventional chemotherapeutic agents.
- |||||||||| Review, Journal: Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease. (Pubmed Central) - Nov 19, 2020
However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.
- |||||||||| bortezomib / Generic mfg., oprozomib (ONX 0912) / Amgen
Journal: Altered proteasome function in right ventricular hypertrophy. (Pubmed Central) - Sep 13, 2020
Moreover, this study provides an improved understanding on the selective activation of the 26S proteasome in RVH that might be driven by the rate-limiting subunit Rpn6. In RVH, Rpn6 therefore represents a more specific target to interfere with proteasome function than the commonly used catalytic proteasome inhibitors.
- |||||||||| dexamethasone / Generic mfg., oprozomib (ONX 0912) / Amgen, pomalidomide / Generic mfg.
Clinical, Journal: Oprozomib, pomalidomide, and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma. (Pubmed Central) - Aug 15, 2020
Safety and pharmacokinetic profiles were concerns with the oprozomib formulation used in this study and need to be improved. Oprozomib-pomalidomide-dexamethasone (2/7 schedule) had encouraging efficacy, supporting an ongoing phase Ib study evaluating new oprozomib formulations for this combination in relapsed/refractory multiple myeloma.
- |||||||||| Darzalex IV (daratumumab) / J&J
Clinical, Review, Journal: Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting 2018. (Pubmed Central) - Aug 5, 2020
Among heavily pretreated MM patients, selinexor and melflufen showed particularly encouraging results. Novel immunotherapeutic approaches including chimeric antigen receptor T cells against B-cell maturation antigen and bispecific antibodies constitute a promising alternative that remains to be evaluated in later-phase studies.
- |||||||||| oprozomib (ONX 0912) / Amgen
Clinical, Journal: Oprozomib in patients with newly diagnosed multiple myeloma. (Pubmed Central) - May 23, 2020
The oprozomib and dexamethasone combination has encouraging activity and could be an important MM therapy if gastrointestinal tolerability is improved. No abstract available
- |||||||||| Review, Journal: The role of ubiquitination in tumorigenesis and targeted drug discovery. (Pubmed Central) - Mar 7, 2020
In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.
- |||||||||| Lamprene (clofazimine) / Novartis
Repurposing Clofazimine As a Novel Drug for the Treatment of PI-Resistant Stem Cell-like Subclones in Myeloma (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_6165;
Based on these results, we propose that CFZ may have strong potential to increase the therapeutic efficacy of PIs when used in combination by specifically targeting MM-CSCs sub cellular population in MM – which we are investigating further. Currently, we are: 1) validating the potency of CFZ (alone or CFZ+PI combination therapy) in primary myeloma cells/PMCs from newly diagnosed patients, followed by 2) bulk mRNA sequencing and 3) single-cell transcriptomic analysis of MM-CSCs in HMCLs and PMCs to evaluate molecular pathways involved in stem-cell based PI-resistance and to characterize PI-resistant sub-cellular stem cell populations based on gene expression signatures using our prediction analysis software SCATTome.
- |||||||||| oprozomib (ONX 0912) / Amgen
Enrollment closed, Combination therapy: INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - Oct 22, 2019
P1b, N=61, Active, not recruiting,
Currently, we are: 1) validating the potency of CFZ (alone or CFZ+PI combination therapy) in primary myeloma cells/PMCs from newly diagnosed patients, followed by 2) bulk mRNA sequencing and 3) single-cell transcriptomic analysis of MM-CSCs in HMCLs and PMCs to evaluate molecular pathways involved in stem-cell based PI-resistance and to characterize PI-resistant sub-cellular stem cell populations based on gene expression signatures using our prediction analysis software SCATTome. Recruiting --> Active, not recruiting
- |||||||||| oprozomib (ONX 0912) / Amgen
Journal: Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors. (Pubmed Central) - Oct 2, 2019
As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t) and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, β5) inhibitory potency (IC50 = 16 nM), low nanomolar anti-proliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development.
- |||||||||| oprozomib (ONX 0912) / Amgen
Trial completion date, Trial primary completion date, Combination therapy: INTREPID-1: Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - Sep 30, 2019
P1b, N=64, Recruiting,
In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, β5) inhibitory potency (IC50 = 16 nM), low nanomolar anti-proliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development. Trial completion date: Sep 2019 --> Dec 2020 | Trial primary completion date: Sep 2019 --> Dec 2020
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