PROTAC Compound Degrading AR-V7 to Overcome Prostate Cancer Resistance

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Solution Overview

Problem

Current androgen receptor (AR) inhibitors, such as enzalutamide, face challenges in treating prostate cancer due to the development of drug resistance caused by androgen receptor splice variants (AR-Vs), particularly AR-V7.

Innovation Solution

Development of a novel compound represented by general formula (I) that inhibits and degrades AR or/and AR-Vs, specifically targeting AR-V7, using a PROTAC or small molecule degrader approach to overcome drug resistance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional androgen receptor inhibitors (enzalutamide, bicalutamide) are used to treat prostate cancer, then initial therapeutic effect is achieved, but drug resistance develops due to androgen receptor splice variants (AR-Vs)

Engineering Contradiction:

Improvetherapeutic effectVSAvoiddrug resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of inhibiting the androgen receptor's function, the invention uses PROTAC technology to induce degradation of the androgen receptor protein itself. This inverted approach targets the root cause of resistance by eliminating the target protein rather than blocking its activity, thereby overcoming the limitations of conventional inhibitors that fail against AR-V variants.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The PROTAC molecule acts as an intermediary that bridges the androgen receptor and E3 ubiquitin ligase. This bifunctional compound contains both an androgen receptor binder and an E3 ligase ligand, facilitating the recruitment of the ubiquitin-proteasome system to degrade the androgen receptor, thus solving the problem of conventional inhibitors being ineffective against splice variants.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If PROTAC technology is used to degrade androgen receptor, then drug resistance is overcome, but molecular complexity increases

Engineering Contradiction:

Improveovercoming drug resistanceVSAvoidmolecular complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The PROTAC molecule is segmented into distinct functional modules: an androgen receptor binding domain, a linker region, and an E3 ubiquitin ligase binding domain. This segmentation allows each component to perform its specific function while maintaining overall molecular organization, making the complex molecule more manageable and designable through modular assembly.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The PROTAC molecule performs multiple functions simultaneously: it binds to the androgen receptor, recruits E3 ubiquitin ligase, facilitates ubiquitination, and directs proteasomal degradation. This multi-functionality is achieved within a single molecular framework, reducing the need for multiple separate agents and simplifying the therapeutic approach despite the inherent molecular complexity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250171417A1Heterocyclic derivative, and composition and pharmaceutical use thereof

Publication Date: 2025.05.29 TIBET HAISCO PHARM CO LTD

AI summary

Disclosed are a compound as represented by general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof and an intermediate thereof; and the use thereof m AR-related diseases such as cancer. B-L-K (I)