SMARCA2-VHL Degraders for Selective Chromatin Modulation
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Solution Overview
Problem
Current approaches lack effective mechanisms to modulate SMARCA2 and SMARCA4 activity, particularly in the context of cancer treatment, where selective inhibition is needed to address mutations and alterations in chromatin remodeling complexes.
Innovation Solution
Development of substituted 3-pyridazinyl-2-phenols and 6-(1,2,4-triazinyl)-2-phenols that selectively bind to SMARCA2 and SMARCA4, facilitating their ubiquitination and targeted degradation, thereby inhibiting their activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current approaches are used to modulate SMARCA2 and SMARCA4 activity, then general chromatin remodeling inhibition is achieved, but selective inhibition of SMARCA2/SMARCA4 is not obtained
Solution Approach 1:
The patent employs PROTAC molecules as intermediary compounds that bridge SMARCA2/SMARCA4 proteins and VHL E3 ligase. These bispecific molecules contain one moiety that binds to SMARCA2/SMARCA4 and another moiety that binds to VHL, facilitating targeted ubiquitination and degradation of SMARCA2/SMARCA4 while leaving other chromatin remodeling proteins unaffected, thus achieving both selectivity and functional modulation.
2Reliability
If selective SMARCA2/SMARCA4 inhibition is implemented, then therapeutic benefit in cancer treatment is improved, but mechanism for targeted degradation must be established
Solution Approach 1:
The invention leverages the cell's own ubiquitin-proteasome system and VHL E3 ligase to achieve targeted degradation of SMARCA2/SMARCA4. The PROTAC molecules recruit endogenous VHL to ubiquitinate SMARCA2/SMARCA4, which are then degraded by the cellular proteasome machinery, eliminating the need for external degradation systems and simplifying the therapeutic mechanism while maintaining high selectivity and efficacy.
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
These compounds demonstrate significant selectivity for SMARCA2 and SMARCA4, offering potential therapeutic benefits in treating various cancers by modulating chromatin remodeling and gene transcription, particularly in solid tumors.
Implementation Method 1
bind to the Switch/Sucrose Non-Fermentable (SWI/SNF) complex and to von Hippel-Lindau (VHL) E3 ligase complex, in particular, to substituted 3-pyridazinyl-2-phenols and 6-(1,2,4-triazinyl)-2-phenol compounds which bind to SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Members 2 and 4 (SMARCA2 and/or SMARCA4) and to VHL, uses thereof, processes for the preparation thereof and compositions comprising said compounds. In certain aspects, the compounds described herein bind to SMARCA2 and VHL contemporaneously to facilitate ubiquitination of SMARCA2 and subsequent targeted degradation of SMARCA2.
Data Source
AI summary
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.