SHP2 Protein Degradation Compounds Using VHL-Mediated Ubiquitination
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Solution Overview
Problem
Current treatments for SHP2-related diseases, such as cancer and tumors, are inadequate, and there is a need for a more effective strategy to inhibit SHP2 activity.
Innovation Solution
Development of a compound that targets and degrades SHP2 protein through ubiquitination by E3 ubiquitin ligase, using a bifunctional compound with a SHP2 binding ligand-linker-VHL ligand structure to induce protein degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If SHP2 inhibition is used to block phosphatase activity, then cancer cell growth is inhibited, but SHP2 protein levels remain unchanged limiting therapeutic effectiveness
Solution Approach 1:
Instead of inhibiting SHP2 phosphatase activity through conventional means, the invention inverts the approach by promoting SHP2 protein degradation through ubiquitination. The compound acts as an E3 ligase recruiter that targets SHP2 for degradation, fundamentally changing the mechanism from activity inhibition to protein level reduction, thereby achieving more reliable therapeutic effectiveness.
Solution Approach 2:
The invention introduces an intermediary mechanism involving E3 ubiquitin ligase recruitment. The compound serves as a mediator that bridges the inhibitor molecule and the SHP2 protein, facilitating ubiquitination and subsequent degradation. This intermediary approach allows for more effective and versatile therapeutic action compared to direct inhibition.
2Productivity
If conventional SHP2 inhibitors are used, then phosphatase activity is blocked, but protein degradation does not occur reducing efficacy
Solution Approach 1:
The invention replaces the mechanical inhibition system (blocking active site) with a biochemical degradation system (ubiquitination pathway). By substituting the inhibition mechanism with a degradation mechanism, the compound achieves higher efficacy by actually reducing SHP2 protein levels rather than merely blocking its activity.
Solution Approach 2:
The invention changes the key parameter from phosphatase activity inhibition to protein level reduction. By modifying the mechanism to target protein stability and promote degradation, the compound achieves superior efficacy. This parameter change from activity-based to level-based inhibition represents a fundamental improvement in therapeutic productivity.
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 compound effectively lowers SHP2 levels, inhibiting its activity and providing a therapeutic approach for SHP2-related diseases with desirable characteristics in stability, solubility, permeability, bioavailability, and pharmacodynamic properties.
Implementation Method 1
a compound having a formula 1 or a pharmaceutically acceptable salt, stereoisomer, isotopomer, solvate, prodrug, or hydrate thereof, as a new SHP2 targeted protein degradation (TPD) compound, that is, a compound capable of targeting and degrading SHP2 protein through ubiquitination of E3 ubiquitin ligase
Data Source
AI summary
The present disclosure provides a compound of a specific chemical structure, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, which has excellent activity in terms of degradation of SHP2 protein. The present disclosure also provides a composition comprising such a compound, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof. The present disclosure also provides medical uses of a composition comprising the compound according to the present disclosure, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of SHP2-associated diseases (for example, cancer). The present disclosure also provides a method for treating or preventing SHP2-associated diseases (for example, cancer), the method comprising administering, to an individual in need of treatment, an effective amount of a composition comprising the compound according to the present disclosure, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.