Chimeric Btk Degrader via Ubiquitin-Proteasome Pathway
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Solution Overview
Problem
Current methods lack effective compounds to selectively degrade Bruton's tyrosine kinase (Btk) proteins, which are crucial for B-cell signaling and play a role in autoimmune disorders, through the ubiquitin-proteasome pathway.
Innovation Solution
Development of compounds with a Btk binding moiety covalently linked to a degradation signaling moiety via a linker, activating the ubiquitination and subsequent degradation of Btk proteins using the ubiquitin-proteasome pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chimeric compounds are designed to activate ubiquitination of Btk, then selective degradation of Btk protein is achieved, but compound design complexity increases
Solution Approach 1:
The patent merges two functional moieties into a single chimeric compound: a Btk binding element that specifically recognizes and binds to Btk protein, and a ubiquitination recognition element (such as a VHL binding element) that recruits the ubiquitin-proteasome system. This merging allows the compound to simultaneously achieve specific target recognition and activation of degradation machinery, resolving the contradiction between achieving reliable selective degradation and maintaining design complexity at a manageable level.
Solution Approach 2:
The chimeric compound acts as an intermediary that bridges the gap between the Btk target protein and the ubiquitin-proteasome degradation system. By incorporating both a Btk binding element and a ubiquitination recognition element, the compound mediates the interaction between these two components, enabling selective degradation without requiring direct modification of either the target protein or the degradation machinery.
2Stability of the object's composition
If covalent linkage is used between Btk binding element and ubiquitination recognition element, then compound stability is improved, but synthesis difficulty increases
Solution Approach 1:
The patent employs covalent linkage between the Btk binding element and the ubiquitination recognition element, fundamentally changing the physical-chemical parameters of the compound structure. This covalent bonding provides stable, permanent connection that prevents dissociation of the functional moieties, ensuring compound stability. While this increases synthesis complexity compared to non-covalent associations, it achieves the desired stability through a well-established chemical bonding approach.
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 selectively degrade Btk proteins, modulating their activity and providing a therapeutic approach for disorders related to Btk, such as autoimmune diseases.
Implementation Method 1
Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation
Implementation Method 2
the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins
Data Source
AI summary
This disclosure relates to compounds of Formula (A): BTK-L-DSM (A) or a pharmaceutically acceptable salt thereof, wherein DSM is a degradation signaling moiety that is covalently attached to the linker L, L is a linker that covalently attaches BTK to DSM, and BTK is a Btk binding moiety represented by Formula (I) or Formula (II) that is covalently attached to linker L: in which all of the variables are as defined in the application. Compounds or pharmaceutically acceptable salts thereof as described herein are capable of activating the selective ubiqitination of Btk proteins via the ubiquitin-proteasome pathways (UPP) and cause degradation of Btk proteins. The present disclosure also provides methods of treating disorders responsive to modulation of Btk activity and/or degradation of Btk with at least one compound described herein.