hRPN13 PROTACs Targeting Pru Domain for Cancer Treatment
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Solution Overview
Problem
There is a scarcity of potent, efficacious, and selective inhibitors and/or PROTACs targeting hRpn13, particularly effective against cancers associated with aberrant hRpn13 activity and variants, including those with the N-terminal Pleckstrin-like receptor for ubiquitin (Pru) domain, which often exhibit cytotoxicity or off-target effects.
Innovation Solution
Development of scaffold molecules and proteolysis targeting chimeras (PROTACs) with specific anti-hRPN13 activity, designed to target hRpn13 and its variants, such as hRpn13-Pru, to effectively treat cancers by inducing cell death and ubiquitination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing hRpn13 binding compounds (RA190, RA183) are used to target hRpn13, then some anti-cancer efficacy is achieved, but they display cytotoxicity and off-target effects due to low specificity
Solution Approach 1:
The patent applies local quality by designing compounds that specifically target the N-terminal Pru domain of hRpn13 rather than the entire protein. This localized targeting approach allows the inhibitor to bind selectively to the Pru domain's ubiquitin-binding site, achieving high specificity for hRpn13 while avoiding off-target effects on other proteins. The selective inhibition of hRpn13's ubiquitin-dependent functions eliminates cytotoxicity associated with non-specific binding.
Solution Approach 2:
The patent employs an intermediary approach by using a PROTAC molecule that mediates between the hRpn13 target and the cellular ubiquitin-proteasome system. The PROTAC consists of three components: an hRpn13-binding moiety that recognizes the Pru domain, a linker, and a recruitment moiety that binds to an E3 ubiquitin ligase. This intermediary mechanism induces targeted ubiquitination and degradation of hRpn13, achieving potent anti-cancer efficacy with high selectivity and without the cytotoxicity of direct inhibitors.
2Productivity
If high dosages of hRpn13 binding compounds are administered to achieve therapeutic effect, then anti-cancer activity increases, but systemic side effects occur
Solution Approach 1:
The patent achieves high anti-cancer activity at low dosages by implementing local quality through selective targeting of the hRpn13 Pru domain. This selective inhibition prevents off-target effects and systemic toxicity, allowing effective treatment at lower concentrations. The specific binding to the Pru domain's ubiquitin-binding site ensures potent anti-cancer activity without the need for high dosages that would cause systemic side effects.
Solution Approach 2:
The PROTAC intermediary mechanism amplifies the therapeutic effect at low dosages by recruiting the cellular ubiquitin-proteasome system to degrade hRpn13. This catalytic mechanism allows a single PROTAC molecule to induce multiple ubiquitination events, achieving high productivity and potent anti-cancer activity at low concentrations without causing systemic toxicity.
3Reliability
If existing hRpn13 inhibitors are used to treat cancers, then some therapeutic effect is achieved, but they require high dosages that may lead to false positives in diagnostic assays
Solution Approach 1:
The patent improves diagnostic assay accuracy by implementing local quality through selective targeting of the hRpn13 Pru domain. This selective inhibition produces a clean therapeutic effect without off-target binding that would cause false positives in diagnostic assays. The specific recognition of the Pru domain's ubiquitin-binding site ensures high measurement precision in both therapeutic and diagnostic contexts.
Solution Approach 2:
The PROTAC intermediary mechanism provides a distinct mode of action that differs from existing inhibitors, reducing cross-reactivity in diagnostic assays. The ubiquitin-proteasome mediated degradation pathway activated by PROTACs produces a unique therapeutic effect that does not interfere with diagnostic assays targeting hRpn13, maintaining both therapeutic efficacy and diagnostic accuracy.
Data Source
AI summary
In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to scaffold molecules having anti-hRPN13 activity, proteolysis targeting chimeras (PROTACs) incorporating the same, methods of making same, pharmaceutical compositions comprising same, and methods of treating cancers involving aberrant hRpn13 activity and/or the presence of hRpn13-Pru/hRpn13 or variants thereof using the same.