Indole Derivatives Modulate EZH2 Enzyme Activity for Cancer Therapy

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Solution Overview

Problem

Current therapies lack effective agents to modulate the activity of methyl modifying enzymes like EZH2, which are implicated in various diseases, including cancer, due to their role in regulating gene expression and epigenetic programs.

Innovation Solution

Development of specific compounds that target EZH2 and EZH1, including those with structural formulas I, II, and III, which can modulate the activity of these enzymes, offering potential therapeutic benefits for diseases associated with their overexpression or mutation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If EZH2 is overexpressed to drive tumor growth and metastasis, then cancer progression is enhanced, but therapeutic intervention opportunities arise

Engineering Contradiction:

Improvetumor growth controlVSAvoidcancer aggressiveness

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and isolates the EZH2 enzyme as a specific therapeutic target from the complex cancer biology system. By developing small molecule inhibitors that specifically bind to EZH2's SET domain, the invention removes the harmful overexpression effect while leaving other cellular functions intact, thereby treating cancer progression without causing systemic side effects

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the activity parameter of EZH2 from overexpressed/high activity to inhibited/low activity states. The small molecule compounds directly modify the enzymatic activity parameter by binding to the SET domain, thereby converting the harmful high-expression state into a therapeutically beneficial low-activity state that suppresses tumor growth and metastasis

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If EZH2 represses tumor suppressor genes, then cancer progression is promoted, but gene expression regulation can be therapeutically targeted

Engineering Contradiction:

Improvegene expression regulationVSAvoidtumor suppressor silencing

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The patent introduces small molecule compounds as intermediary substances that mediate between the EZH2 enzyme and its substrate (histone H3). These compounds act as molecular mediators that block the interaction between EZH2 and histone H3 at the lysine 27 residue, thereby preventing the repressive epigenetic modification without directly interacting with the tumor suppressor genes themselves

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention applies preliminary anti-action by inhibiting EZH2 activity before it can repress tumor suppressor genes. The small molecule inhibitors bind to EZH2 and prevent the methylation reaction from occurring, thereby preemptively blocking the epigenetic silencing of tumor suppressors like E-cadherin, DAB2IP, and RUNX3 before it can contribute to cancer progression

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentUS9969716B2Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof

Publication Date: 2018.05.15 CONSTELLATION PHARMA INC

AI summary

Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.