RPN13-Targeting Spirocyclic-Guanidine Compounds for Solid Tumors
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Solution Overview
Problem
Existing proteasome inhibitors, such as bortezomib and carfilzomib, are ineffective against solid tumors due to poor drug penetration, short half-life, and neurotoxicity, and lead to resistance and progression in multiple myeloma patients.
Innovation Solution
Development of spirocyclic-guanidine compounds that target the RPN13 subunit of the 19S regulatory particle, inhibiting the proteasome and triggering apoptosis in cancer cells, with improved solubility and safety profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide-based proteasome inhibitors are used, then proteasome inhibition activity is achieved, but drug penetration into solid tumors is poor and half-life is short
Solution Approach 1:
The patent changes the chemical structure from peptide-based to small molecule spirocyclic-guanidine compounds, fundamentally altering the pharmacokinetic parameters to achieve improved half-life and drug penetration while maintaining proteasome inhibition activity
Solution Approach 2:
The invention creates a composite molecular structure combining spirocyclic scaffold with guanidine functional groups, achieving both structural stability for extended half-life and functional activity for proteasome inhibition
2Reliability
If peptide-based proteasome inhibitors are used, then proteasome inhibition activity is achieved, but neurotoxicity and off-target effects increase
Solution Approach 1:
The patent extracts and eliminates the problematic peptide backbone that causes neurotoxicity, replacing it with a small molecule spirocyclic-guanidine structure that maintains proteasome inhibition activity without the harmful off-target effects
Solution Approach 2:
The invention uses small molecule compounds with short structural sequences (compared to peptide-based drugs) that achieve the required biological activity without the persistent toxic effects associated with longer peptide structures
3Duration of action of stationary object
If prolonged treatment with licensed proteasome inhibitors is given, then cancer treatment is sustained, but resistance and disease progression develop
Solution Approach 1:
Instead of continuing the same mechanism of action that leads to resistance, the patent inverts the approach by targeting a different mechanism (RPN13 ubiquitin receptor) that has not been previously targeted, thereby maintaining treatment efficacy over time
Solution Approach 2:
The invention introduces dynamic adaptability in treatment strategy by switching to a novel mechanism of action that can overcome resistance development, allowing the treatment to remain effective as cancer cells adapt to therapy
4Object-affected harmful factors
If spirocyclic-guanidine compounds are developed, then solubility and safety are improved, but binding specificity to RPN13 must be maintained
Solution Approach 1:
The patent applies local quality by incorporating specific functional groups (guanidine) at specific positions within the spirocyclic structure to achieve both improved solubility/safety and maintained binding specificity to the RPN13 target
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The spirocyclic-guanidine compounds effectively accumulate polyubiquitinated proteins in cancer cells, inducing apoptosis and inhibiting tumor growth, demonstrating oral bioavailability and reduced toxicity.
Implementation Method 1
these molecules work as proteasome inhibitors and bind to the RPN13 subunit of the 19S regulatory particle
Implementation Method 2
inhibiting the proteasome and triggering apoptosis in cancer cells
Data Source
AI summary
The invention of the instant application discloses spirocyclic guanidine compounds of general formula (I), shown below, and their use in methods of treating cancer