Selective HDAC Inhibitors for Hormone-Refractory Prostate Tumors

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Solution Overview

Problem

Current HDAC inhibitors lack selectivity for prostate malignancies, leading to toxicity and low potency, and existing anti-androgens are ineffective against hormone refractory prostate cancer.

Innovation Solution

Development of novel HDAC inhibitors with specific structures, such as compounds of Formula (I), targeting prostate cancer cells to enhance selectivity and efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current HDAC inhibitors are used to treat prostate cancer, then HDAC activity is inhibited, but selectivity for prostate malignancies is poor leading to toxicity and low potency

Engineering Contradiction:

Improveselectivity for prostate malignanciesVSAvoidtoxicity and low potency

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing HDAC inhibitors with specific molecular structures (Formula I and Formula II) that contain prostate cancer-targeting moieties. These structures enable the inhibitors to selectively bind to HDAC enzymes in prostate malignancies while sparing other tissues, thereby improving selectivity and reducing off-target toxicity.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying key structural parameters of HDAC inhibitors, including the hydroxamic acid group, cyclic imine ring, and aromatic substituents. These structural modifications optimize the inhibitors' binding affinity to prostate cancer HDAC enzymes while minimizing interactions with normal cells, thus enhancing potency and reducing toxicity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If existing anti-androgens are used to treat hormone refractory prostate cancer, then androgen receptor binding is achieved, but effectiveness against hormone refractory prostate cancer is insufficient

Engineering Contradiction:

Improveeffectiveness against hormone refractory prostate cancerVSAvoidtreatment efficacy

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies inversion by shifting the therapeutic strategy from targeting the androgen receptor (which fails in hormone refractory cancer) to targeting histone deacetylase enzymes. This alternative approach addresses the epigenetic mechanisms that drive hormone refractory prostate cancer progression, thereby overcoming the limitations of conventional anti-androgen therapy.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent uses HDAC inhibitors as intermediary agents that modulate gene expression through epigenetic mechanisms. By inhibiting HDAC activity, these compounds alter chromatin structure and gene transcription, indirectly affecting androgen receptor signaling and other pathways involved in hormone refractory prostate cancer without directly competing with androgen binding.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250313538A1Histone Deacetylase (HDAC) Inhibitors Targeting Prostate Tumors

Publication Date: 2025.10.09 GEORGIA TECH RES CORP

AI summary

An exemplary embodiment of the present disclosure provides a compound of Formula (I):where A, Y,and W are as described herein. The present disclosure is also directed to pharmaceutical compositions comprising these compounds and methods of using these compounds as histone deacetylase inhibitors for the treatment of a disease or disorder, particularly for the treatment of cancer.