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Selective 20S proteasome inhibition for multiple myeloma therapy

Project description

Towards more selective treatments for mulitple myeloma

Multiple myeloma (MM) is the most common haematological malignancy, affecting plasma cells, the antibody-producing cells of our body. Proteasome inhibitors (PIs) are the gold standard drug treatment for MM, but they have been associated with non-specific activity and adverse side effects. Previous work by the EU-funded 20SInhibitor project led to the design of an artificial protein based on the structure of the newly identified 20S PIs, the catalytic core regulators (CCRs), which selectively target the 20S proteasome. Collectively, the researchers' work will drive the design of novel peptide inhibitors that specifically target the 20S proteasome, exhibiting greater selectivity for cancer cells and fewer systemic side effects. During 20SInhibitor project, researchers will carry out actions to take their innovation from the laboratory to the next phase in developing therapy for MM.

Objective

Multiple myeloma (MM) is a cancer of plasma cells, that is incurable, and the second most common form of blood cancer. Proteasome inhibitors (PIs) are considered a mainstay in the treatment of MM and mantle cell lymphoma (MCL). Current drugs, based on PIs however, target the chymotrypsin-like activity of the 20S proteasome, and inhibit the activities of both the 20S and 26S proteasomes. Thus, it is possible that selective drug intervention specifically inhibiting only the 20S proteasomes will reduce toxicity, and minimize the deleterious side effects of the current therapeutic regimens.

Our preliminary work revealed a family of 20S proteasome inhibitors, which we termed Catalytic Core Regulators (CCRs) that selectively target the 20S proteasome rather than the 26S complex. Based on sequence motif and structural elements of the CCRs we have designed an artificial protein that is capable of inhibiting the 20S proteasome. We anticipate that these findings will lead to the design of synthetic proteins, peptides or peptidomimetic compounds targeting cancer cells more specifically. This specificity will pose the compounds in an attractive light for using them in various therapeutic applications.

What is exciting from the commercialization perspective, is that pharmaceutical research has switched to revisit the use of peptides as therapeutics. Pharmaceutical companies have seen the development of peptides as a promising direction to lower their risk position. Overall, peptide therapeutics have a 20% chance of receiving regulatory approval, a probability that is 50% higher than that for the approval of small molecules, which form the basis of so called traditional drugs.

In the project, we will carry out actions, which will equip us with the sufficient IP protection strategy, business strategy, industry networks and initial contacts for taking the innovation out from the laboratory to next phase in developing therapy first for MM and MCL later on.

Host institution

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution
€ 150 000,00
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost
€ 150 000,00

Beneficiaries (1)