Fused Ring CRBN Binders for Targeted Protein Degradation in Tumors
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Solution Overview
Problem
Current small molecule compounds targeting the CRBN-E3 ligase interaction for treating tumors beyond hematological malignancies are limited, necessitating the development of new compounds that can regulate CRBN and degrade specific proteins effectively.
Innovation Solution
Development of a class of fused ring compounds or their pharmaceutically acceptable salts, characterized by specific structural features, which can bind to the E3 ligase to induce protein degradation, thereby addressing the need for effective treatment of various tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If existing small molecule compounds (thalidomide, lenalidomide, pomalidomide) are used to target CRBN for treating hematological tumors, then good efficacy is achieved in hematological tumors, but the ability to treat other types of tumors (solid tumors) is limited
Solution Approach 1:
The patent modifies the chemical structure of existing CRBN-targeting compounds by introducing a fused ring system with specific substituents (R1, R2, R3, R4) and variable parameters (m, n, p). This structural parameter change enables the compound to regulate CRBN effectively while expanding its applicability to solid tumors beyond the original hematological tumor indication, thus resolving the contradiction between versatility and efficacy.
Solution Approach 2:
The invention creates a composite molecular structure by fusing a heteroaromatic ring with a carbocyclic or heterocyclic ring system, forming a new fused ring compound that combines the CRBN-regulating capability of existing immunomodulators with enhanced properties for treating diverse tumor types. This composite structure achieves both reliable efficacy and broader adaptability.
2Adaptability or versatility
If small molecule compounds are developed to degrade specific proteins through CRBN regulation, then therapeutic benefit for various tumors is achieved, but the complexity of compound structure increases
Solution Approach 1:
The fused ring compound is designed as a segmented molecular structure with distinct functional regions: a heteroaromatic ring portion, a carbocyclic or heterocyclic ring portion, and variable substituent groups (R1-R4). This segmentation allows the molecule to maintain CRBN-binding capability while providing specific interaction sites for inducing degradation of target proteins, achieving high adaptability without excessive overall complexity.
Solution Approach 2:
The patent designs a universal fused ring scaffold that can regulate CRBN and induce degradation of multiple different target proteins through appropriate selection of substituents (R1, R2, R3, R4) and ring types. This multi-functional design enables a single compound structure to achieve broad protein degradation capability, reducing the need for multiple separate compounds for different targets.
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 fused ring compounds demonstrate potential in regulating CRBN and degrading specific proteins, offering therapeutic benefits for a range of tumors, including solid tumors and hematological malignancies.
Implementation Method 1
Ubiquitin-proteasome system (UPS) is one of the important protein degradation pathways in human cells, which mainly includes two processes: ubiquitination of substrate protein and degradation of ubiquitin-labeled protein by proteasome
Data Source
AI summary
The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and the salt thereof, and uses thereof, which are particularly suitable for preparing a medicament for treating or preventing abnormal cell proliferation diseases.