PROTAC Derivatives with Functional Handles for Chemical Conjugation/Modification
This technology introduces novel multifunctional compounds that act as proteolysis targeting chimeras (PROTACs), which are hetero-bifunctional molecules designed to selectively degrade disease-associated proteins inside cells. PROTACs chemically link a protein-binding ligand with an E3 ligase-binding ligand, enabling targeted protein ubiquitination and subsequent destruction via the proteasome. The disclosed invention improves existing PROTAC technology by incorporating new ligand chemistries, optimized linkers, and expanded E3 ligase recruitment strategies that enhance selectivity, degradation efficiency, and drug-like properties.
Researchers
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proteolysis targeting chimeric molecules (protacs) with functional handles and uses thereof
United States of America | Granted | 12,042,513
Technology
The PROTAC molecule structure consists of two functional binding regions: one that binds a target protein and another that binds an E3 ubiquitin ligase, connected by a chemical linker. Upon entering the cell, the PROTAC brings the target protein and E3 ligase into proximity, enabling ubiquitination of the target and its degradation by the proteasome and then releasing the PROTAC for further reaction. The invention supports the use of various E3 ligase binders (e.g., cereblon, VHL) and novel linker architectures to optimize ternary complex formation and cooperative binding. The compounds also include a functional group, termed the first reaction handle, that enables conjugation to delivery vehicles or polymeric structures, allowing improved and targeted delivery of the molecule to the protein site. These modifications enhance cooperative binding, improve cell permeability, and broaden the range of E3 ligases that can be employed for targeted degradation.
Problem Addressed
This technology addresses key limitations of early-generation PROTACs, including limited E3 ligase options, poor biodistribution, suboptimal pharmacokinetics, and inefficient ternary complex formation. Traditional PROTACs often rely on a narrow set of E3 ligases like VHL or cereblon, which can limit tissue specificity and lead to resistance. Furthermore, early-generation PROTACs often suffer from poor solubility, weak binding, and off-target effects. This technology overcomes these limitations by enabling the formation of conjugates and polymers that improve delivery and pharmacological properties while expanding the chemical space for ligands and linkers.
Advantages
- Broader E3 ligase recruitment through novel ligand designs, expanding tissue targeting and resistance management options.
- Improved ternary complex formation via linker optimization for stronger, cooperative binding between target and E3 ligase.
- Enhanced selectivity and reduced off-target effects through refined ligand chemistries and binding affinities.
- Better pharmacokinetic properties by incorporating features that improve cell permeability and bioavailability.
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