delanzomib (CEP-18770) / Teva - LARVOL DELTA

Inhibitors of the ubiquitin‑proteasome system rescue cellular levels and ion transport function of pathogenic pendrin (SLC26A4) protein variants. (PubMed, Int J Mol Med) - "Inhibition of the UPS with investigational (MG132) or clinical (bortezomib, delanzomib, or carfilzomib) proteasome inhibitors rescued the expression, plasma membrane targeting, and ion transport function of pathogenic pendrin variants, while inhibition of the lysosomal/autophagosomal pathway was ineffective. Among the compounds tested, carfilzomib rescued the ion transport of pendrin p.R409H to wild‑type levels. These findings suggest that targeting specific molecular players within the UPS can rescue the expression and activity of pathogenic variants of the pendrin protein, which represents a novel therapeutic concept for Pendred syndrome/DFNB4."

Journal • Otorhinolaryngology • Targeted Protein Degradation • SLC26A4

An automated positive selection screen in yeast provides support for boron-containing compounds as inhibitors of SARS-CoV-2 main protease. (PubMed, Microbiol Spectr) - "Among those were three previously only predicted in silico; the boron-containing proteasome inhibitors bortezomib, delanzomib, and ixazomib. We have thus demonstrated that our platform can screen large numbers of chemicals to find potential inhibitors of a viral protease. Importantly, the platform can be modified to detect protease targets from other emerging viruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • SPECC1

The Proteasome Inhibitor CEP-18770 Induces Cell Death in Medulloblastoma. (PubMed, Pharmaceutics) - "Furthermore, we discovered that CEP-18770 and cisplatin, a current component of MB therapy, exhibit a synergistic apoptotic effect. This paper shows that CEP-18770 holds potential as an adjunctive treatment for MB tumors, thereby paving the way for more targeted and less toxic therapeutic strategies."

Journal • Brain Cancer • Hematological Malignancies • Medulloblastoma • Multiple Myeloma • Oncology • Solid Tumor

Increasing the therapeutic vulnerability of heterogenous cell phenotypes within prostate cancer (AACR 2024) - "Tested compounds with differential sensitivity between aggressive and non-aggressive cells were those inhibiting histone deacetylase (vorinostat, fimepinostat, and pracinostat), proteasomes (bortezomib, delanzomib, ixazomib), topoisomerases (gimatecan and daunorubicin), and other compounds identified independently by us targeting nicotinamide phosphoribosyl transferase (FK866) and DNA (bleomycin). Funding was provided by the University of Arizona Cancer Center (NCI-P30 CA23074 and NCI-R01 CA159406) and by the Partnership in Native American Cancer Prevention at the University of Arizona (U54CA143924) and Northern Arizona University (U54CA143925). Collaborators at NCATS were supported by the intramural research program."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDH1 • CLDN4 • CLDN7 • KRT6A • ZEB1

Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer. (PubMed, Cell Death Discov) - "Monotherapy identified nine effective drugs (bortezomib, carfilzomib, cisplatin, delanzomib, docetaxel, epoxomicin, MLN-2238, MLN-9708, and nedaplatin) across all cell lines. PIs (e.g., bortezomib, delanzomib, and epoxomicin) were highly potent drugs in TNBC cells, of which bortezomib and delanzomib inhibited the chymotrypsin-like activity of the 20 S proteasome by 100% at 10 µM. Moreover, several potent 2-drug combinations (e.g., bortezomib+nedaplatin and epoxomicin+epirubicin) that killed virtually 100% of cells were also identified. Although HCC1806- and MCF-7-derived xenografts treated with bortezomib+nedaplatin and carboplatin+paclitaxel were smaller, HCC1806 cells frequently metastasized to the trunk region. Taken together, we show that PIs used in combination with platinum agents or topoisomerase inhibitors exhibit increased efficiency with almost 100% inhibition in TNBC cell lines, indicating that PIs are therefore promising compounds to use as combination..."

Journal • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies. (PubMed, Front Chem) - "Delanzomib and tibalosin, the top two drugs with docking scores of -10.643 and -10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of -67.96 and -50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA...The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery."

Journal • Oncology

Proteasome inhibition in combination with immunotherapies: State-of-the-Art in multiple myeloma. (PubMed, Blood Rev) - "In this paper we briefly highlight essential clinical elements relating to proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib. A high number of patients develop PI resistance. Thus, we also review new generation PIs, such as marizomib, oprozomib (ONX0912) and delanzomib (CEP-18770) and their combinations with immunotherapies."

Combination therapy • Journal • Review • Bone Marrow Transplantation • Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology • Transplantation

Delanzomib (CEP-18770) in Combination With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=11 | Completed | Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. | Terminated ➔ Completed

Combination therapy • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials? (PubMed, Front Endocrinol (Lausanne)) - "We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. 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..."

Journal • Review • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Rare Diseases • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Potential Efficacy of Proteasome Inhibitor, Delanzomib, for the Treatment of Renal Fibrosis. (PubMed, Biol Pharm Bull) - "Treatment with Dz decreased the expression levels of the actin-alpha-2 (ACTA2) and collagen-type-1-alpha-1 (COL1A1) genes in the kidney, which are common fibrosis markers. These results suggest that Dz might be a compound that suppresses renal fibrosis by inducing selective cell death of myofibroblasts, although further investigation is required."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Renal Disease • Transplantation • ACTA2 • COL1A1

Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer (SABCS 2022) - "Both aspirin and tamoxifen drugs are good examples of successful drug repurposing in oncology... TNBC cell lines were generally more sensitive to proteasome inhibitors with significantly reduced cell viability than clinically relevant drugs, e.g. paclitaxel...Using the drug sensitivity screening results for single drugs, IDACombo predicted potent drug combinations for different combinations of bortezomib, carboplatin, carfilzomib, delanzomib, docetaxel, doxorubicin, epirubicin, epoxomicin, MLN-2238, MLN-9708, and nedaplatin. In summary, some proteasome inhibitors (e.g. bortezomib) had a substantial impact on TNBC cell survival. These findings indicate that proteasome inhibitors, together with other forms of chemotherapy, may be further explored as a novel complement treatment for TNBC."

Breast Cancer • Hematological Malignancies • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR • PGR

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro. (PubMed, Int J Mol Sci) - "The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons."

Journal • Preclinical • Pain • NEUROG1

Delanzomib, a Novel Proteasome Inhibitor, Combined With Adalimumab Drastically Ameliorates Collagen-Induced Arthritis in Rats by Improving and Prolonging the Anti-TNF-α Effect of Adalimumab. (PubMed, Front Pharmacol) - "In conclusion, delanzomib combined with adalimumab may be a potential therapeutic approach for treating rheumatoid arthritis. The initial finding that the PK interaction occurred between delanzomib and adalimumab may have clinical relevance for patients who simultaneously take proteasome inhibitors and anti-TNF-α therapeutic proteins."

Journal • Preclinical • Hematological Malignancies • Immunology • Inflammatory Arthritis • Multiple Myeloma • Oncology • Rheumatoid Arthritis • Rheumatology • CRP • IL6

The interaction between S100A2 and KPNA2 mediates NFYA nuclear import and is a novel therapeutic target for colorectal cancer metastasis. (PubMed, Oncogene) - "Through the S100A2/KNPA2 complex, depending on its interaction with S100A2, NFYA is transported to the nucleus and inhibits the transcriptional activity of E-cadherin, which in turn promotes CRC metastasis. Targeting the S100A2/KPNA2 binding sites with the specific inhibitor delanzomib is a potential therapeutic approach for CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDH1

Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions. (PubMed, Pharmaceutics) - "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."

Journal • Oncology • Oral Cancer • Targeted Protein Degradation

Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib (AACR 2018) - "The fact that oprozomib bound to the 20S proteasome more slowly than any of the other drugs may be the reason, in part, that it is less toxic. Support: CIHR; a Canada Research Chair in Drug Development."

Oncology

Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. (PubMed, Drug Resist Updat) - "However, due to its limitations, second generation proteasome inhibitors (PIs) like carfilzomib, ixazomib, oprozomib, delanzomib and marizomib were introduced which displayed clinical activity in bortezomib-resistant tumors. 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."

Journal • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Targeted Protein Degradation

Charge transfer reaction mechanisms of epoxyketone and boronated peptides at glassy carbon and boron doped diamond electrodes. (PubMed, J Electroanal Chem (Lausanne)) - "The redox behavior of proteasome inhibitors, epoxyketone and boronated peptides carfilzomib, oprozomib and delanzomib was investigated by voltammetric methods using glassy carbon and boron doped diamond electrodes. The oxidation reaction occurred at the amino group close to the pyridine moiety of delanzomib with the transfer of one electron and one proton whereas the reduction process takes place at pyridine ring in a two-electrons two-protons mechanism. Redox mechanisms were proposed and the implications on the proteasome inhibition discussed."

Journal • Targeted Protein Degradation

Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2α/ATF4/CHOP pathway. (PubMed, Am J Transl Res) - "For limited clinical benefits and acquired resistance by sorafenib, new therapeutic strategies and molecular targets for the treatment of advanced hepatocellular carcinoma (HCC) are urgently needed. Compared to control group, 3 and 10 mg/kg of delanzomib significantly reduced the tumor volume by 33.1% and 87.2% respectively after 3 weeks treatment, with no significant change on the body weight and the level of serum biochemical indexes including ALT, AST and BUN. In conclusion, delanzomib could exhibit good pre-clinical antitumor effects against HCC cells by inducing ERS and activating the PERK/eIF2α/ATF4/CHOP pathway, as potential drug candidate on treatment of advanced HCC patients."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CASP3 • CCNB1 • CDK1

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells. (PubMed, Sci Rep) - "The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate...Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST...In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while..."

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Delanzomib, a novel proteasome inhibitor, sensitizes breast cancer cells to doxorubicin-induced apoptosis. (PubMed, Thorac Cancer) - "The combined regimen of the proteasome inhibitor delanzomib with Dox chemotherapy may become an effective strategy for breast cancer therapy."

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