BRM-Targeting PROTAC Compounds for SMARCA2 Degradation
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Solution Overview
Problem
Existing treatments for cancers with SMARCA4 mutations or deficiencies, such as non-small cell lung cancer, are hindered by the inability to effectively target and modulate SMARCA2, a key protein in these cancers, due to the challenges of targeting protein-protein interactions with small molecules.
Innovation Solution
Development of bifunctional compounds, known as PROTACs, that recruit SMARCA2 to E3 ubiquitin ligases like VHL for degradation, utilizing a protein targeting moiety (PTM) and an E3 ubiquitin ligase binding moiety (ULM) linked by a chemical linker (L), to modulate targeted ubiquitination and inhibit SMARCA2 activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecules are used to target protein-protein interactions, then therapeutic intervention is possible, but the ability to effectively bind and modulate the target protein is limited due to large contact surfaces and shallow grooves
Solution Approach 1:
The patent employs PROTAC molecules as intermediary compounds that mediate between the E3 ubiquitin ligase and the target protein SMARCA2. The PROTAC contains two binding moieties: one that binds to the E3 ligase (VHL) and another that binds to the target protein (SMARCA2), facilitating therapeutic intervention despite the challenges of targeting protein-protein interactions with small molecules
Solution Approach 2:
The invention creates composite molecular structures by combining different functional elements into a single PROTAC molecule. The compound integrates an E3 ligase binding moiety, a linker, and a target protein binding moiety, forming a composite structure that achieves both binding capabilities simultaneously
2Reliability
If bifunctional PROTAC compounds are developed to recruit SMARCA2 to E3 ubiquitin ligases, then targeted degradation and inhibition of SMARCA2 is achieved, but the complexity of the compound structure increases
Solution Approach 1:
The PROTAC compound is segmented into distinct functional modules: an E3 ligase binding moiety (VHL ligand), a linker component, and a target protein binding moiety (SMARCA2 binder). This segmentation allows each component to perform its specific function while maintaining overall molecular functionality
Solution Approach 2:
The PROTAC molecule performs multiple functions simultaneously: it binds to the E3 ubiquitin ligase, recruits the target protein SMARCA2, facilitates ubiquitination, and directs the complex to the proteasome for degradation. This multi-functionality is achieved within a single molecular entity
Data Source
AI summary
The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.