Phthalazinone PROTAC Degrader for Androgen Receptor Resistance

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Solution Overview

Problem

Current treatments for metastatic castration-resistant prostate cancer (mCRPC) are limited, with existing drugs like abiraterone and enzalutamide eventually leading to drug resistance due to mutations in the androgen receptor (AR).

Innovation Solution

Development of proteolysis targeting chimeras (PROTAC) technology to create selective AR degraders (SARDs) that interact with the AR and the ubiquitin-proteasome system, leading to the degradation of the AR and overcoming drug resistance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional endocrine therapy (abiraterone, enzalutamide) is used to treat prostate cancer, then initial treatment effectiveness is achieved, but drug resistance develops due to androgen receptor mutations

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidduration of drug sensitivity

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent replaces conventional small molecule antagonists that bind to the androgen receptor with PROTAC molecules that recruit the ubiquitin-proteasome system to degrade the receptor. This substitutes a binding-inhibition mechanism with a degradation-elimination mechanism, overcoming resistance caused by mutations that affect small molecule binding but not PROTAC function.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent changes the fundamental parameter of AR suppression from transient inhibition (small molecule binding) to permanent elimination (protein degradation). By converting the therapeutic mechanism from reversible binding to irreversible degradation, the treatment overcomes resistance that develops against reversible inhibitors.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If androgen receptor is suppressed through small molecule antagonists, then tumor growth is inhibited initially, but mutated AR converts antagonists into agonists causing drug resistance

Engineering Contradiction:

Improvetumor growth inhibitionVSAvoiddrug resistance development

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent replaces the small molecule antagonist binding mechanism with a PROTAC-mediated ubiquitination and degradation mechanism. This substitution eliminates the problem of mutated AR converting antagonists into agonists because PROTACs induce degradation rather than binding, making the therapeutic effect independent of AR mutation status.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If proteolysis targeting chimeras (PROTAC) technology is used to degrade androgen receptor, then drug resistance is overcome, but molecular design complexity increases

Engineering Contradiction:

Improveovercoming drug resistanceVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The PROTAC molecule is segmented into distinct functional domains: an AR-binding domain, a linker region, and a ubiquitin-proteasome system-recruiting domain. This segmentation allows independent optimization of each component and simplifies the overall design process by treating the complex molecule as an assembly of functional modules.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses the ubiquitin-proteasome system as an intermediary mechanism to achieve AR degradation. Rather than designing a complex direct degradation pathway, the PROTAC molecule leverages the cell's existing proteolytic machinery, simplifying the molecular design by using a natural intermediary system.

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 use of PROTAC technology for AR degradation offers a potential solution to overcome drug resistance in mCRPC, providing a new approach for treating advanced prostate cancer.

Implementation Method 1

proteolysis targeting chimeras (PROTAC) technology to afford a type of selective AR degraders (SARDs)... The PROTAC technology mainly relies on an intracellular ubiquitin-proteasome system... The ubiquitinated proteins are degraded by the proteasome system inside the cells

Methodology Applied

Scientific EffectProteolysis: Decomposition (biological)

Data Source

PatentUS12234223B2Phthalazinone compound, and preparation method therefor and medical use thereof

Publication Date: 2025.02.25 SHANGHAI JEMINCARE PHARMACEUTICALS CO LTD

AI summary

Disclosed are a phthalazinone compound, and a preparation method therefor and the medical use thereof. In particular, disclosed are a compound as represented by formula (I), and a pharmacodynamically acceptable salt, and the use of the compound as an androgen receptor (AR) for degradation.