Covalent Molecular Glue Stabilizers for 14-3-3 Protein Targeting
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Solution Overview
Problem
Current cancer drug discovery faces challenges in targeting the 'undruggable' proteome, as most proteins lack well-defined binding pockets, and existing therapeutic modalities like PROTACs are limited by molecular weight and affinity requirements, while there is a need for systematic approaches to discover molecular glues that can inhibit oncogenic transcription factors and kinases.
Innovation Solution
Development of novel covalent chemoproteomic platforms and 14-3-3-based molecular glues that target the cysteine C38 of 14-3-3 proteins, enabling the sequestration and inhibition of oncogenic transcription factors like ERα, YAP, and TAZ, using drug-like chemical scaffolds that comply with drug development criteria and enhance interactions with proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If heterobifunctional PROTACs are used to induce protein proximity for degradation, then therapeutic benefit is achieved for some targets, but molecular weight increases and drug-like properties deteriorate
Solution Approach 1:
The invention extracts and eliminates the unnecessary second functional domain (protein-targeting ligand for degradation) from the heterobifunctional PROTAC structure, retaining only the essential molecular glue component that induces proximity between 14-3-3 and the target protein, thereby reducing molecular weight while maintaining therapeutic efficacy
Solution Approach 2:
The invention introduces 14-3-3 proteins as an intermediary mediator that facilitates the interaction between the small-molecule drug and undruggable target proteins, enabling therapeutic action without requiring the drug molecule itself to directly bind the target with high affinity
2Reliability
If heterobifunctional IPTMs are used to target undruggable proteins, then functional manipulation is achieved, but requirement for protein-targeting ligand with decent affinity increases complexity
Solution Approach 1:
The invention removes the requirement for a protein-targeting ligand with decent affinity from the heterobifunctional IPTM structure, retaining only the simple molecular glue component that stabilizes the 14-3-3 target protein, thereby simplifying ligand structure while achieving functional manipulation of undruggable targets
Solution Approach 2:
The invention employs 14-3-3 proteins as an intermediary that simplifies the drug design by providing a stable binding target (14-3-3) rather than requiring direct binding to the undruggable target protein, thus reducing ligand structure complexity
3Reliability
If natural product scaffolds like fusicoccin A are used to enhance 14-3-3 interactions, then sequestration of oncogenic proteins is achieved, but synthetic accessibility deteriorates
Solution Approach 1:
The invention changes the chemical parameters and structural characteristics of the molecular glue scaffold from complex natural products like fusicoccin A to simpler fully synthetic structures that maintain the ability to enhance 14-3-3 interactions while being much more accessible through standard pharmaceutical synthesis
Solution Approach 2:
The invention replaces expensive and difficult-to-synthesize natural product scaffolds with cheaper, easily manufactured synthetic small molecules that can be produced at scale using conventional pharmaceutical manufacturing processes
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 approach identifies drug-like molecular glues that effectively stabilize or enhance interactions with 14-3-3 proteins, inhibiting oncogenic transcription factors and kinases, demonstrating potential for broad therapeutic targeting of undruggable cancer targets by sequestering them outside the nucleus.
Implementation Method 1
cysteine-reactive covalent ligands that covalently react with Cys38 of the 14-3-3 protein
Data Source
AI summary
A novel drug discovery platform identifies compounds for therapeutically targeting 14-3-3 proteins and sequestering and inhibiting the activities of various disease-relevant proteins. Therapeutic compositions comprise a scaffold for therapeutically targeting 14-3-3 proteins and sequestering and inhibiting the activities of various disease-relevant proteins.