CRBN Modulator Selectivity to Avoid ASS1 Degradation
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Solution Overview
Problem
Current targeted protein degradation agents, such as molecular glues and PROTACs, face liabilities due to off-target interactions with argininosuccinate synthetase 1 (ASS1), leading to potential drug side effects and reduced efficacy for therapeutically relevant targets.
Innovation Solution
Development of compounds that selectively bind to cereblon (CRBN) without engaging ASS1, promoting interactions with therapeutically relevant substrates like Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), Pegasus (IKZF5), CSNK1A, CK1a, and ZFP91, while minimizing ASS1 recruitment, ubiquitination, and degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If molecular glues and PROTACs are used to degrade target proteins, then therapeutic efficacy is improved, but off-target interactions with ASS1 cause side effects and reduce reliability
Solution Approach 1:
The patent modifies the chemical structure of molecular glues and PROTACs to change their binding parameters, creating compounds that selectively bind to CRBN with high affinity while avoiding ASS1 interaction. This structural optimization resolves the contradiction by maintaining therapeutic efficacy through effective CRBN binding while eliminating harmful off-target effects.
Solution Approach 2:
The patent uses CRBN as an intermediary protein to mediate the degradation of target proteins. By designing compounds that specifically engage CRBN rather than directly targeting the disease protein, the system achieves selective degradation while avoiding direct interaction with ASS1, thus resolving the off-target effect issue.
2Productivity
If compounds bind to CRBN to induce protein degradation, then target protein elimination is achieved, but recruitment of ASS1 into protein complexes causes detrimental effects
Solution Approach 1:
The patent introduces local quality differentiation by designing compounds with specific molecular features that selectively interact with particular regions of CRBN responsible for substrate recruitment, while avoiding interaction with ASS1 binding sites. This localized interaction optimization maintains high protein degradation productivity while preventing harmful ASS1 recruitment.
Solution Approach 2:
The patent segments the CRBN interaction interface into distinct functional regions, designing compounds that engage only the regions necessary for inducing substrate ubiquitination and degradation, while leaving ASS1 interaction regions unengaged. This segmentation allows selective protein degradation without triggering harmful ASS1-related effects.
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 reduce off-target effects, enhancing therapeutic efficacy by favoring degradation of relevant targets and minimizing ASS1-related liabilities, thus reducing side effects and improving treatment outcomes.
Implementation Method 1
promote, induce, enhance, and/or stabilize small molecule-protein (or small molecule-protein complex) interactions
Implementation Method 2
promote ubiquitination and/or degradation of ASS1
Implementation Method 3
Targeted protein degradation, by way of eliminating a target protein in cells by routing it to the proteasome
Data Source
AI summary
Methods of assessing the efficacy of an agent in treating a disease or disorder are provided that include determining whether the agent causes, or inhibits, direct or indirect recruitment and/or ubiquitination and/or degradation of argininosuccinate synthetase 1 (ASS1).