Photo-Switchable PROTAC for Light-Regulated Protein Degradation

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Solution Overview

Problem

Current PROTAC technologies face challenges in regulating the degradation of ABL protein levels, leading to potential excessive degradation and the need for a reversible and adjustable approach to down-regulate BCR-ABL and ABL proteins in K562 leukemia cells.

Innovation Solution

A proteolysis targeting chimeric molecule with a specific chemical structural formula, allowing for adjustable and reversible degradation of BCR-ABL and CRBN proteins, featuring a synthesis method and photo-isomerization activity for light-regulated degradation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If PROTAC molecules are used to degrade BCR-ABL and ABL proteins, then the expression level of BCR-ABL is effectively down-regulated, but excessive degradation of ABL protein occurs leading to abnormal cell cycle function

Engineering Contradiction:

ImproveBCR-ABL protein expression levelVSAvoidabnormal cell cycle function caused by excessive ABL degradation

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent applies dynamics by introducing a photo-switchable group that allows the PROTAC molecule to dynamically change its degradation activity. The molecule can be activated or deactivated through light irradiation, enabling precise temporal and spatial control over ABL protein degradation. This resolves the contradiction by allowing effective BCR-ABL down-regulation while preventing excessive ABL degradation through reversible control.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent changes the physical-chemical state of the PROTAC molecule by incorporating a photo-switchable group that undergoes isomerization upon light irradiation. This parameter change (molecular conformation) directly controls the degradation activity, allowing the system to switch between active and inactive states. This resolves the technical contradiction by enabling precise control of degradation intensity and duration.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If traditional small molecule inhibitors are used, then the mechanism is simple, but they cannot effectively act on nonmedicinal proteins compared to PROTAC technology

Engineering Contradiction:

Improveeffectiveness on nonmedicinal proteinsVSAvoidPROTAC molecule structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the PROTAC molecule into distinct functional modules: a BCR-ABL binding domain, a degradation domain (CRBN ligand), and a photo-switchable group. This modular structure allows for targeted degradation while maintaining controllable complexity. The segmented design enables effective action on nonmedicinal proteins while organizing the molecular complexity into manageable functional units.

Inventive Principle:

Principle #1Segmentation

3Adaptability or versatility

If ABL gene is knocked out to study cell function, then cell cycle function can be analyzed, but it causes abnormal cell cycle function and cannot be used for reversible regulation

Engineering Contradiction:

Improvereversible regulation capabilityVSAvoidnormal cell cycle function

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies periodic action through light-controlled activation and deactivation cycles. By irradiating with light at specific times, the PROTAC molecule can be periodically activated to degrade ABL protein and then deactivated to allow recovery. This periodic control enables reversible regulation of ABL expression, maintaining normal cell cycle function while allowing study of ABL's role in cell processes.

Inventive Principle:

Principle #19Periodic action

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 proteolysis targeting chimeric molecule effectively inhibits the expression of BCR-ABL and CRBN proteins in leukemia cells, providing a basis for drug development with excellent photo-isomerization activity and selective targeting of BCR-ABL positive leukemia cells.

Implementation Method 1

The proteolysis targeting chimeric molecule with n=3 has excellent photo-isomerization activity, and can be used in preparation of the reagents or drugs for light-regulated degradation of BCR-ABL and/or CRBN protein

Methodology Applied

Scientific EffectPhoto-isomerization: Photochromism

Data Source

PatentUS11504385B2Proteolysis targeting chimeric molecule, preparation method, and application

Publication Date: 2022.11.22 CHINA PHARM UNIV

AI summary

It discloses a proteolysis targeting chimeric molecule, a preparation method and an application thereof. The proteolysis targeting chimeric molecule provided by the disclosure can inhibit the expression of BCR-ABL and/or CRBN protein in BCR-ABL and/or CRBN positive leukemia K562 cells to varying degrees, and thus can be used to prepare drugs for treating BCR-ABL and/or CRBN positive leukemia, wherein the proteolysis targeting chimeric molecule with n=3 has excellent photo-isomerization activity, and can be used in preparation of the reagents or drugs for light-regulated degradation of BCR-ABL and/or CRBN protein. The disclosure also provides a method for synthesizing the series of proteolysis targeting chimeric molecules.