USP7 Inhibitors Stabilize p53 to Reduce Cancer Toxicity
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Solution Overview
Problem
Current therapeutic strategies for cancer treatment, particularly those targeting the ubiquitin-proteasome pathway, face limitations such as toxicity and drug resistance, with specific DUB inhibitors yet to be developed for clinical use despite their potential in addressing deregulated HDM2 and p53-related cancers.
Innovation Solution
Development of novel compounds, specifically those inhibiting ubiquitin C-terminal hydrolase 7 (USP7) using specific chemical structures that act as inhibitors of deubiquitylating enzymes, which are designed to stabilize p53 and enhance immune surveillance against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If proteasome inhibitors like bortezomib are used to treat cancer, then cancer treatment efficacy is improved, but toxicity and drug resistance increase
Solution Approach 1:
The patent extracts and targets a specific enzyme (USP7) within the ubiquitin-proteasome pathway rather than inhibiting the entire proteasome system. By isolating and inhibiting this specific deubiquitylating enzyme, the therapy achieves cancer treatment efficacy while avoiding the broad toxicity and resistance issues associated with proteasome inhibitors.
Solution Approach 2:
The invention applies local quality by designing compounds that specifically target USP7 with high selectivity. The chemical structure is optimized to interact precisely with the active site of USP7, creating a localized therapeutic effect that spares other cellular processes, thereby reducing off-target toxicity.
2Object-affected harmful factors
If DUB inhibitors are developed to target USP7, then specificity and reduced toxicity are improved, but development complexity increases
Solution Approach 1:
The patent segments the ubiquitin-proteasome pathway by focusing on a single enzymatic step catalyzed by USP7. This segmentation allows for simplified drug design targeting a specific mechanism, reducing the complexity compared to targeting the entire proteasome system while maintaining therapeutic specificity.
Solution Approach 2:
The invention employs parameter changes by systematically modifying chemical structures (varying R1-R6 substituents, aromatic ring configurations, and linker groups) to optimize binding affinity and selectivity for USP7. This structured approach to parameter optimization manages development complexity through methodical exploration of chemical space.
Data Source
AI summary
The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs) and/or desumoylating enzymes. In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 7 or ubiquitin specific peptidase 7 (USP7). The invention further relates to the use of DUB or desumoylating inhibitors in the treatment of cancer. Described herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c and R1d each independently represent hydrogen, optionally substituted C1-C6 alkyl or R1a and R1b together form an optionally substituted C3-C6 cycloalkyl ring, or R1c and R1d together form an optionally substituted C3-C6 cycloalkyl ring; A is a 5 membered nitrogen-containing aromatic ring and is substituted with at least one optionally substituted 5 to 10 membered monocyclic or bicyclic heteroaryl or aryl ring attached through an optional linker.