Summary:

The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for three small molecules that target hRpn13, an overexpressed protein in certain cancers.

Description of Technology:

Over 35,000 new cases of multiple myeloma are diagnosed each year in the US. Standard of care and experimental therapies include monoclonal antibodies, immunomodulatory drugs, proteasome inhibitors and corticosteroids. While these therapies can be effective, a majority of patients experience relapse within four years. New proteasome-targeting drugs are needed to improve current myeloma treatments.

Proteasome inhibitors function by interfering with a cell’s normal protein recycling process and induce apoptosis via multiple mechanisms. FDA-approved proteasome inhibitors exist with indications for the treatment of liquid cancers, specifically multiple myeloma and mantle-cell lymphoma. However, these drugs can induce dose-limiting toxicities. It is hypothesized that targeting ubiquitin receptors upstream of the 20S proteasome may lead to less toxic therapies, such as targeting the 19S proteasome regulatory region associated within ubiquitin receptor Rpn13.

Inventors at the NCI have generated three small molecules, XL44, XL69, XL80 that target ubiquitin receptor hRpn13. hRpn13Pru is produced in certain cancer cell types. XL44, XL69, and XL80 deplete it reliably without fusion to a known ligand related to ubiquitination complexes, suggesting a glue-like mechanism of depletion. XL44 induces apoptosis in a hRpn13-dependent manner, but can restrict cell viability independently of hRpn13, specifically via depletion of KEN box proteins. Early in vivo studies show reduced tumor size in xenograft multiple myeloma models. The inventors have developed an oral formulation.

Potential Commercial Applications:

* Multiple Myeloma therapeutic

* Mantle Cell therapeutic

Competitive Advantages:

* Oral formulation

* Lower toxicity than currently approved proteasome inhibitors