Small-Molecule Translation Modulators for Protein Synthesis Inhibition
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Solution Overview
Problem
Existing small molecule therapeutics primarily focus on binding to target proteins to inhibit or activate their function, lacking effective modulation of protein homeostasis, particularly in altering protein synthesis and turnover.
Innovation Solution
Development of small molecules that inhibit the translation machinery to modulate protein synthesis, including compounds of Formula (I) and their pharmaceutically acceptable salts, which can be administered to modulate protein synthesis in cells or biological samples.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecules bind to target proteins to inhibit or activate their function, then the target protein's function is modulated, but the ability to modulate protein homeostasis and alter protein synthesis is lost
Solution Approach 1:
The patent employs molecular glues as intermediary compounds that facilitate the interaction between E3 ligases and target proteins. These small molecule mediators induce the formation of ternary complexes, enabling the target protein to be recognized and degraded by the cellular proteasome system, thereby achieving modulation of protein homeostasis and synthesis
2Ease of operation
If existing small molecule therapeutics focus on binding to target proteins, then specific protein function is altered, but effective modulation of protein synthesis and turnover is not achieved
Solution Approach 1:
The invention utilizes the universal cellular degradation machinery (proteasome system and E3 ligases) to achieve modulation of various target proteins. By designing small molecules that can induce degradation of different target proteins through common degradation pathways, the system achieves multi-functionality and broad applicability across diverse protein targets while maintaining operational simplicity
Data Source
AI summary
The present disclosure provides compounds, and pharmaceutically acceptable salts thereof, which are useful for modulating protein synthesis. The present disclosure also provides pharmaceutical compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, and methods of treating or preventing diseases or disorders (e.g., diseases or disorders associated with BCL-2, MYC, CCND1, MCL-1, ALK, KRAS-G12D) by administering to a subject in need thereof the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.