USP28 Inhibitors via Segmentation and Parameter Changes
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Solution Overview
Problem
Current methods for developing small molecule inhibitors targeting ubiquitin-specific protease 28 (USP28) have been limited in yielding drug-like compounds with good selectivity, and there is a need for novel and potent inhibitors to address USP28's role in tumorigenesis and immune responses.
Innovation Solution
A compound of formula (I) or its pharmaceutically acceptable salt, specifically designed to inhibit USP28, is administered to treat diseases associated with USP28, including cancer, by targeting the enzyme and disrupting its activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high throughput diversity library screening is employed for DUB inhibitor development, then screening efficiency is improved, but selectivity and drug-likeness of resulting compounds deteriorates
Solution Approach 1:
The patent segments the DUB enzyme family into distinct classes (cysteine proteases and zinc metalloproteases) and further divides cysteine proteases into six families based on sequence homology. This segmentation allows targeted screening strategies for each subclass, improving selectivity by focusing on specific enzyme families rather than screening all DUBs uniformly, thus resolving the contradiction between screening efficiency and compound selectivity.
Solution Approach 2:
The patent applies local quality by developing selective inhibitors tailored to specific DUB subclasses rather than creating universal DUB inhibitors. Each inhibitor is designed with specific structural features that target particular enzyme families (e.g., USP28 inhibitors with specific sulfonamide moieties), allowing high selectivity for the intended target while maintaining reasonable screening efficiency through focused library design.
2Productivity
If substrate or ligand-based design strategies are used for DUB inhibitors, then hit identification is improved, but development of potent and selective inhibitors deteriorates
Solution Approach 1:
The patent employs parameter changes by systematically modifying molecular parameters of lead compounds to optimize inhibitor potency and selectivity. This includes adjusting the chemical structure of sulfonamide-based inhibitors, modifying substituent groups (R1-R6, X1, Z1-Z3), and optimizing binding interactions with USP28. These parameter optimizations transform initial hits into potent and selective inhibitors, resolving the contradiction between hit identification efficiency and final inhibitor quality.
Data Source
AI summary
The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutical composition comprising the compound of formula (I). The present composition also relates to methods treating a disease or disorder associated with ubiquitin-specific protease 28 (USP28), methods of treating cancer, and methods of inhibiting USP28.