Candidate Small Molecule Proteasome Inhibitors with Antitumor Properties

Unmet Need
Cancer cells differ critically from normal cells, e.g., higher metabolic rates. Proteasomes play a pivotal role in managing excessive metabolism and maintaining protein homeostasis, as the continued over-accumulation of mis-folded proteins is toxic to cells.

Several proteasome inhibitors have proven efficacious against hematologic malignancies, although drug resistance, significant neurological side effects and inactivity against solid tumors remain challenging. As such, there is a compelling need for alternative mechanisms in developing additional proteasome inhibitors.

Technology Overview
Hopkins inventors have developed potent inhibitors against the ubiquitin-proteasome system by targeting the ubiquitin receptor RPN13 within proteasome’s 19S regulatory particle, utilizing a rational development approach to modify substituents around the core unit of RA190. After multiple tests, one compound emerged as a promising molecule based on potency, pharmacodynamics and its reduction of tumor burden and prolongation of the survival of mice in an orthotopic human ovarian cancer xenograft model. Since the leading proteasome therapeutic drug, bortezomib, has not proven effective against ovarian and other solid cancers, further exploration of this new class of RPN13 inhibitors, potentially in combination with doxorubicin, is warranted because their novel mechanism of action.

Stage of Development
In vivo mouse model data is available

Publications
Manuscript in preparation
 

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