Bifunctional TYK2 Degraders for Selective JAK Family Targeting
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Solution Overview
Problem
Current treatments for immunological and inflammatory disorders face challenges in selectively targeting TYK2 due to the high homology of the ATP active site within the JAK family, leading to non-specific effects and the inability to modulate TYK2 effectively.
Innovation Solution
Development of hetero-bifunctional compounds that recruit TYK2 to an E3 ubiquitin ligase, such as cereblon, for targeted ubiquitination and subsequent proteasomal degradation, utilizing a moiety that binds to the pseudokinase domain of TYK2 and a ligase binding moiety to induce degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule drugs bind to the ATP active site of TYK2, then TYK2 activity is inhibited, but non-specific effects occur due to high homology within the JAK family
Solution Approach 1:
The invention extracts the catalytic kinase domain (JH1) from the full TYK2 protein and expresses it as a standalone soluble protein. This extracted domain serves as a specific bait in pull-down assays, allowing selective identification of compounds that bind to TYK2's catalytic domain without cross-reactivity from other JAK family members. The extraction principle enables specific inhibition validation by isolating the functional domain responsible for catalytic activity.
Solution Approach 2:
The invention focuses on the pseudokinase domain (JH2) of TYK2 as a specific binding site for compound identification. By expressing only the JH2 domain as a soluble protein, the assay selectively identifies compounds that bind to this specific local region of TYK2. This local quality approach allows differentiation of compounds with specific affinity for TYK2's pseudokinase domain versus those that bind promiscuously to multiple JAK family members.
2Reliability
If TYK2 is targeted for degradation using bifunctional compounds, then TYK2 protein levels are reduced, but the complexity of the degradation system increases
Solution Approach 1:
The invention employs an E3 ubiquitin ligase (such as cereblon or von Hippel-Lindau protein) as an intermediary in the TYK2 degradation system. The bifunctional compound acts as a bridge, with one end binding to TYK2 and the other end binding to the E3 ligase. This intermediary approach enables targeted degradation through the cell's natural ubiquitin-proteasome system, reducing the need for complex external degradation machinery while maintaining high specificity for TYK2.
Solution Approach 2:
The invention leverages the cell's endogenous proteasome degradation system to execute TYK2 degradation. Instead of introducing an entirely external degradation mechanism, the bifunctional compound recruits existing cellular components (E3 ligases and proteasomes) to perform the degradation function. This self-service principle simplifies the overall system by utilizing the cell's own machinery for protein degradation, reducing the complexity of externally imposed degradation systems.
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 compounds effectively reduce TYK2 protein levels, providing therapeutic benefits for conditions like autoimmune diseases and inflammatory disorders by specifically targeting and degrading TYK2.
Implementation Method 1
recruit endogenous proteins to an E3 ubiquitin ligase for ubiquitination and subsequent degradation in the proteasome degradation pathway
Data Source
AI summary
Bifunctional compounds, which find utility as modulators of non-receptor tyrosine kinase 2 (TYK2), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds TYK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.