BTK PROTAC Degrader Composition for Potent Protein Knockdown

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Solution Overview

Problem

There is a need for more potent BTK inhibitors or degraders that can effectively target BTK via alternative strategies, such as through degradation, to treat autoimmune and inflammatory diseases and cancers.

Innovation Solution

Development of PROTAC compounds that act as BTK degraders or inhibitors, comprising specific heterobifunctional molecules capable of binding to BTK and E3 ligase, leading to the ubiquitination and subsequent degradation of the BTK protein.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional BTK inhibitors are used, then BTK activity is inhibited, but the inhibitory potency is insufficient and alternative strategies are needed

Engineering Contradiction:

ImproveBTK inhibition effectivenessVSAvoidneed for alternative strategies

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of using conventional inhibitors that block BTK activity, the patent employs PROTAC degraders that induce ubiquitination and proteasomal degradation of BTK, fundamentally inverting the mechanism from activity blockade to protein destruction, thereby achieving more potent and sustained inhibition

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The PROTAC compound comprises a heterobifunctional molecule combining a BTK-binding ligand and an E3 ligase-binding ligand connected by a linker, creating a composite structure that simultaneously engages both targets to facilitate degradation

Inventive Principle:

Principle #40Composite materials

2Reliability

If PROTAC compounds are developed to degrade BTK, then degradation potency is improved, but the molecular complexity increases

Engineering Contradiction:

ImproveBTK degradation potencyVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The PROTAC molecule is segmented into distinct functional modules: a BTK-binding ligand portion, an E3 ligase-binding ligand portion, and a linker connecting them, allowing each segment to be optimized independently while maintaining overall functionality

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The linker serves as an intermediary component that bridges the BTK-binding ligand and E3 ligase-binding ligand, enabling proper spatial arrangement and simultaneous engagement of both targets without requiring overly complex molecular architecture

Inventive Principle:

Principle #24Intermediary (Mediator)

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 provide a potent mechanism to inhibit and degrade BTK, offering therapeutic benefits in treating diseases mediated by BTK, including cancers, by effectively reducing BTK activity and promoting its degradation.

Implementation Method 1

comprising specific heterobifunctional molecules capable of binding to BTK and E3 ligase, leading to the ubiquitination and subsequent degradation of the BTK protein

Methodology Applied

Scientific EffectUbiquitination:

Data Source

PatentUS20260028345A1BTK degrader and use thereof

Publication Date: 2026.01.29 ASCENTAGE PHARMA SUZHOU CO LTD

AI summary

The present disclosure relates to compounds that function as degraders or inhibitors of BTK. The present disclosure further relates to pharmaceutical compositions comprising them, and to their use in the treatment of diseases mediated by BTK, such as cancer.