Novel Bis-benzylidine Piperidone-based Proteasome Inhibitors with Anticancer Activity

Unmet Need
A hallmark of many human cancers is the proteasomal degradation of tumor suppressor proteins, leading to apoptosis arrest and sustained cell proliferation. Yet, to date, the therapeutic use of proteasome inhibitors is impeded by the grave side effects and emergence of disease resistance. This invention provides the novel small molecule proteasome inhibitor RA190, which utilizes a distinct mode of action, thus presenting a powerful new therapeutic especially efficacious for the treatment of refractory cervical and ovarian cancers and multiple myeloma (MM).
 
Technology Overview
Johns Hopkins researchers have discovered a novel proteasome inhibitor, valuable as a potent new therapeutic for malignancies dependent on proteolytic degradation, including ovarian and cervical cancer and MM. Malignant cells generally have elevated levels of proteasome activity, rendering them particularly sensitive to proteasome inhibitors; however, high drug toxicity and increasing disease resistance present major obstacles to the efficient clinical use of current inhibitors. Here, inventors discovered RA190, a biocompatible, irreversible small molecule proteasome inhibitor covalently binding a novel cellular target, namely proteasomal ubiquitin receptor RPN13. Importantly, RA190 efficiently induces p53-mediated and p53-independent apoptosis in refractory MM, cervical and ovarian cancer cell lines as well as their parental lines. Moreover, whilst showing notably improved anti-tumor activity in vivo, drug toxicity is significantly reduced. Together, the high efficiency and bioavailability, as well as capability to overcome resistance make this compound an excellent new therapeutic for the targeted treatment of diseases dependent on proteasomal function, including MM, cervical and ovarian cancers.
 
Stage of Development
Pre-Clinical
 

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