Targeted PROTAC Conjugates for Tissue-Selective Protein Degradation
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Solution Overview
Problem
PROTACs face challenges with poor druggability, membrane permeability, physicochemical properties, and limited tissue selectivity, complicating their in vivo applications and targeting properties.
Innovation Solution
Conjugating PROTACs with targeted ligands to improve targeting properties and druggability, utilizing specific cell surface proteins like FOLR1, TRPV6, PSMA, LHRH, EGFR, Her2, Trop2, Her3, Claudin18.2, and c-Met, and linking them with a proteolysis targeting chimera to enhance selectivity and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PROTAC molecular weight is increased to include both target protein ligand and E3 ligase ligand, then protein degradation capability is improved, but membrane permeability and druggability deteriorate
Solution Approach 1:
The PROTAC molecule is divided into two separate components: a cell penetrating peptide (CPP) for cellular delivery and a degrader molecule for protein degradation. This segmentation allows each component to be optimized independently - the CPP handles membrane permeability while the degrader maintains degradation capability, resolving the contradiction between molecular size and membrane penetration.
Solution Approach 2:
A cell penetrating peptide acts as an intermediary carrier that facilitates the delivery of the PROTAC degrader molecule across the cell membrane. The CPP temporarily binds to the degrader, enables transmembrane transport, and then releases the active degrader inside the cell, solving the membrane permeability issue without compromising degradation function.
2Adaptability or versatility
If PROTAC structure is made more complex to target multiple proteins, then versatility is improved, but selectivity to specific tissues and cells deteriorates
Solution Approach 1:
The cell penetrating peptide is designed with specific local properties (positive charge, amphipathic structure) that enable selective interaction with cell membranes and uptake mechanisms in target tissues. This local optimization of the CPP structure provides tissue-selective delivery while the degrader portion maintains its protein-specific binding capability, achieving both versatility and selectivity.
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
Enhances the targeting and druggability of PROTACs, overcoming drug resistance and undruggable targets, while maintaining low toxicity and improving tissue selectivity.
Implementation Method 1
The cell penetrating peptide is capable of mediating cellular uptake of the PROTAC molecule or the conjugate compound
Implementation Method 2
the chimera can bring the target protein and E3 ligase closer and form a ternary complex, target protein-PROTAC-E3 ligase
Implementation Method 3
ubiquitin approaches E3 ligase due to the action of ubiquitin-conjugating enzyme E2 and is further attached to the target protein depending on E3 ligase (ubiquitination of the target protein)
Implementation Method 4
The ubiquitinated target protein will be recognized and degraded by proteasome, and thus the level of the target protein is selectively reduced
Data Source
AI summary
A conjugate compound capable of targeting and binding to cells and degrading abnormal or unwanted proteins, use thereof, and a linker compound useful for the preparation of said conjugate compound.