Heterobifunctional Molecules Degrade TEAD via Ternary Complex
Solution Overview
Problem
There is a need for improved cancer treatment options that target the TEAD protein to alter the Hippo pathway's function, as current therapies are limited in effectively inhibiting TEAD and YAP-TEAD or TAZ-TEAD interactions.
Innovation Solution
The development of bifunctional degrader molecules that utilize the ubiquitin proteasome system (UPS) to selectively degrade TEAD proteins by forming a ternary complex with the target protein, an E3 ubiquitin ligase, and the degrader molecule.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule degraders are used to target TEAD proteins, then the Hippo pathway function can be altered and cancer treatment efficacy improved, but the complexity of the therapeutic approach increases compared to conventional inhibitors
Solution Approach 1:
The degrader molecule is segmented into two distinct functional parts: an E3 ligase-binding motif and a TEAD-binding motif. This segmentation allows each part to independently perform its specific function - the E3 ligase motif recruits the ubiquitin ligase while the TEAD-binding motif targets the transcription factor, together achieving protein degradation through the UPS pathway.
Solution Approach 2:
The small molecule degrader acts as an intermediary that bridges the E3 ubiquitin ligase and the TEAD protein. By forming a ternary complex where the degrader molecule simultaneously binds both the E3 ligase and TEAD, it mediates the interaction between these two proteins, enabling ubiquitination and subsequent degradation of TEAD through the cellular UPS machinery.
2Manufacturing precision
If bifunctional degrader molecules are designed to form ternary complexes with E3 ligase and TEAD, then selective degradation of TEAD proteins is achieved, but the molecular structure complexity increases
Solution Approach 1:
The bifunctional degrader molecule is divided into two distinct functional modules: an E3 ligase-binding motif that specifically recognizes and binds to the E3 ubiquitin ligase, and a TEAD-binding motif that targets the TEAD transcription factor. This segmentation enables precise spatial positioning of both binding interactions within the ternary complex, achieving selective degradation of TEAD proteins while maintaining manageable molecular structure through modular design.
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
This approach provides a novel therapeutic modality for cancer treatment by effectively degrading TEAD proteins, thereby disrupting the Hippo pathway's dysregulation associated with cancer, leading to potential therapeutic benefits in treating hyperproliferative disorders.
Implementation Method 1
Small molecule degraders are increasingly utilized as tools to examine the functional roles of proteins and emerged as a novel therapeutic modality. Operating at the post-translational level, these molecules provide the potential for differentiated biological responses in comparison to classical inhibitors and expand the repertoire of methods for protein knock down beyond genetic approaches (e.g.: knock-out, siRNA). Degrader molecules provide an example of a chemical genetic technique capable of more generally targeting the proteome. These chimeric molecules are designed to induce the degradation of their target proteins via the ubiquitin proteasome system (UPS), thereby eliminating pre-existing proteins. The UPS is the major intracellular pathway for protein degradation in which a series of enzymes known as E1s (ubiquitin activating enzymes), E2s (ubiquitin conjugating enzymes) and E3s (ubiquitin ligases) carry out covalent linkage of the 9 kDa, 76 amino acid protein ubiquitin to a target protein. Subsequent enzymatic reactions result in the formation of a polyubiquitin chain, which targets the protein for degradation by the 26S proteasome.
Implementation Method 2
inhibition of TEAD and YAP-TEAD or TAZ-TEAD protein-protein interaction by pharmacological intervention appears to be a reasonable and valuable strategy to prevent and/or treat cancer and other hyperproliferative disorders and diseases associated with the dysfunction of the Hippo pathway
Data Source
AI summary
Compounds of the formula (I) Q1-Q2-Q3 (I) in which Q1, Q2 and Q3 have the meanings indicated in claim 1, degrade target proteins, and can be employed, inter alia, for the treatment of diseases and conditions mediated by such target proteins.