Bisphenol Ether Compounds Targeting AR Splice Variants

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Solution Overview

Problem

Current treatments for prostate cancer, particularly metastatic castration-resistant prostate cancer, are inadequate due to the limitations of existing androgen receptor (AR) inhibitors, which fail to effectively target constitutively active AR splice variants and are resistant to certain therapies.

Innovation Solution

Development of bisphenol ether compounds with halogenated phenyl groups and/or sulfone linking groups that modulate AR activity, including targeting the N-terminal domain, to inhibit or degrade the AR, thereby providing a novel approach for treating prostate cancer and other androgen-related conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing androgen receptor inhibitors are used to treat prostate cancer, then treatment is provided for standard prostate cancer, but the treatment fails against constitutively active AR splice variants and castration-resistant forms

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidtarget coverage range

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical structure parameters of AR inhibitors by introducing specific substituents at defined positions in the molecular framework. These structural parameter changes enable the compounds to bind to and modulate both full-length AR and truncated AR splice variants, expanding target coverage while maintaining treatment reliability across different prostate cancer forms including castration-resistant cases

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The disclosed bisphenol ether compounds are designed to perform multiple functions: they can inhibit both full-length androgen receptors and truncated AR splice variants, and they can modulate AR activity through multiple mechanisms including binding to the N-terminal domain. This multi-functionality allows a single compound to address diverse prostate cancer types that previously required different treatment approaches

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Ease of operation

If conventional AR inhibitors are used, then simplicity of administration is maintained, but resistance to therapy develops in castration-resistant prostate cancer

Engineering Contradiction:

Improveadministration simplicityVSAvoidtherapy resistance

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent employs composite molecular structures combining bisphenol ether frameworks with specific halogenated phenyl groups and sulfone linking groups. This composite structural approach creates compounds with enhanced biological activity that can overcome therapeutic resistance while maintaining the simplicity of oral or systemic administration characteristic of conventional AR inhibitors

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS11919874B2Bisphenol derivatives and their use as androgen receptor activity modulators

Publication Date: 2024.03.05 THE UNIV OF BRITISH COLUMBIA

AI summary

Compounds having a structure of Formula I:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, R11a, R11b, R11c, R11d, and X, are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of subjects in need thereof, including prostate cancer are also provided.