delanzomib (CEP-18770)

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 therapy for TNBC.

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.

P1/2, N=11, Completed, Teva Branded Pharmaceutical Products R&D, Inc. | Terminated --> Completed

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 the therapeutic response, and to ultimately improve patients' outcome and survival.

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.

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.

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.