PROTAC BTK Degradation Overcoming C481S Resistance

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for diseases associated with Bruton's Tyrosine Kinase (BTK), including wild-type and C481S mutant forms, face challenges due to resistance and the inability to effectively target and modulate mutant BTKs, leading to relapse and poor outcomes in CLL patients.

Innovation Solution

Development of bifunctional or proteolysis targeting chimeric (PROTAC) compounds that recruit endogenous proteins to E3 ubiquitin ligases for degradation, specifically targeting BTK and other proteins like VHL, cereblon, and IAPs to modulate their activity and levels, using moieties that bind to these ligases and target proteins to facilitate degradation and inhibition.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule inhibitors are used to target BTK, then kinase activity is inhibited, but resistance develops due to mutations (e.g., C481S) and the inability to effectively target mutant forms

Engineering Contradiction:

Improveeffectiveness against mutant BTKVSAvoidability to target both wild-type and mutant BTK

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of inhibiting BTK kinase activity directly, the invention inverts the approach by recruiting endogenous BTK to an E3 ubiquitin ligase complex, leading to proteasomal degradation of the protein. This inversion from functional inhibition to protein destruction overcomes resistance because it targets the protein itself rather than its active site, rendering kinase mutations irrelevant to therapeutic efficacy.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention introduces an intermediary bifunctional PROTAC molecule that bridges BTK and the E3 ligase complex. This intermediary contains a BTK-binding moiety and an E3 ligase-recruiting moiety connected by a linker, facilitating the recruitment process without requiring direct interaction between BTK and the degradation machinery, thus enabling versatile targeting of various BTK forms.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of manufacture

If direct BTK inhibition is used, then kinase activity is suppressed, but the approach fails to account for protein-protein interaction complexity and shallow binding interfaces

Engineering Contradiction:

Improvesimplicity of inhibition mechanismVSAvoidcomplexity of protein-protein interaction targeting

Core Design Contradiction:

Ease of manufactureVSDevice complexity

Solution Approach 1:

The complex task of targeting protein-protein interactions is segmented into manageable components within the PROTAC molecule: a BTK-binding domain, a linker region, and an E3 ligase-recruiting domain. Each segment can be independently optimized and characterized, simplifying the development process while addressing the inherent complexity of PPI targeting through modular design.

Inventive Principle:

Principle #1Segmentation

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 PROTAC compounds effectively degrade and inhibit target proteins, including BTK, regardless of mutations, offering a potential solution for persistent disease control and overcoming resistance, as demonstrated by their ability to reduce BTK levels and inhibit kinases in various cancer types.

Implementation Method 1

This complex ubiquitinates a number of other proteins... The PROTAC compounds effectively degrade and inhibit target proteins... offering a potential solution for persistent disease control

Methodology Applied

Scientific EffectUbiquitination:

Data Source

PatentUS11028088B2Modulators of BTK proteolysis and methods of use

Publication Date: 2021.06.08 YALE UNIVERSITY

AI summary

The present disclosure relates to bifunctional compounds, which find utility as modulators of Burton's Tyrosine Kinase (BTK). In particular, the present disclosure is directed to bifunctional compounds. One end of a bifunctional compound includes a Von Hippel-Lindau, Cereblon, Inhibitors of Apotosis Proteins, or Mouse Double-Minute Homolog 2 ligand that binds to the respective E3 ubiquitin ligase. The other end of a bifunctional compound includes a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein can be treated or prevented with compounds and compositions of the present disclosure.