Histone Lysine Demethylase Inhibitor Design via AKG Pocket Interaction

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Solution Overview

Problem

Current inhibitors for histone lysine demethylases, particularly KDM4 proteins, face challenges such as poor cell-penetrating ability and high cytotoxicity, limiting their effectiveness in cancer therapy.

Innovation Solution

A method involving computer-aided design to generate compounds that interact with specific sites of histone lysine demethylases, including alpha-ketoglutarate, methylated lysine, and a NIQ site, followed by in vitro or in vivo assays to identify potent inhibitors like 1,5-bis[(E)-2-(3,4-dichlorophenyl)ethenyl]-2,4-dinitrobenzene, which selectively targets KDM4A/4B subfamily.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If AKG analogue inhibitors (OGAs, PD2s, 8HQs) are used to inhibit KDM4 proteins, then demethylase activity is inhibited, but cell-penetrating ability is poor and cytotoxicity is high

Engineering Contradiction:

Improvedemethylase inhibition efficacyVSAvoidcytotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of AKG analogue inhibitors by changing molecular parameters such as replacing the AKG core with alternative scaffolds (e.g., isoxazole, pyrazole, triazole rings), adjusting R1-R6 substituents, and modifying molecular weight, logP, and topological polar surface area to reduce cytotoxicity while maintaining demethylase inhibition efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces prodrug formulations and cell-permeable delivery systems as intermediaries to transport the inhibitor compounds across cell membranes, thereby improving cell-penetrating ability without requiring direct administration of the active inhibitor form

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If AKG analogue inhibitors are used to inhibit KDM4 proteins, then demethylase activity is inhibited, but cell-penetrating ability is poor

Engineering Contradiction:

Improvedemethylase inhibition efficacyVSAvoidcell-penetrating ability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent optimizes molecular parameters including reducing molecular weight to below 500 Da, adjusting logP to enhance membrane permeability, and minimizing topological polar surface area to improve passive diffusion across cell membranes while preserving target binding affinity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs prodrug strategies and cell-permeable carriers as intermediary systems to facilitate intracellular delivery of the inhibitor compounds, enabling them to reach the cytosolic target without requiring direct cell penetration of the parent compound

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11279966B2Method for identifying compound for inhibiting an activity of a histone lysine demethylase

Publication Date: 2022.03.22 NATIONAL TSING HUA UNIVERSITY

AI summary

A method for identifying a compound that inhibits an activity of a histone lysine demethylase, in which the compound interacts with three sites of a pocket of the histone lysine demethylase generated by using a computer program, an alpha-ketoglutarate (AKG), a methylated lysine, and a NIQ.