Mithramycin SK SDK Derivatives for Selective ETS Inhibition

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Solution Overview

Problem

Current therapies for Ewing sarcoma and other cancers targeting ETS transcription factors, such as FLI1 and ERG, are ineffective due to toxicity issues and lack of selectivity, necessitating the development of less toxic and more selective analogues of mithramycin (MTM) to improve treatment outcomes.

Innovation Solution

The development of mithramycin short side chain ketone (SK) and diketone (SDK) derivatives, synthesized through inactivation of the mtmW gene in Streptomyces argillaceus, which exhibit increased activity and selectivity against cancer cells by modulating the activity of aberrant ETS transcription factors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If mithramycin (MTM) is used to inhibit ETS transcription factors in Ewing sarcoma, then anti-cancer activity is improved, but toxicity to non-Ewing cells increases due to inhibition of Sp transcription factors

Engineering Contradiction:

Improveanti-cancer activityVSAvoidtoxicity to non-Ewing cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by modifying specific regions of the mithramycin molecule (positions 3 and 4 on ring C) to create derivatives with altered binding specificity. The MTM-3,4 derivative selectively targets ETS transcription factors while sparing Sp transcription factors, achieving local optimization of binding properties to reduce off-target toxicity while maintaining anti-cancer activity against Ewing sarcoma cells

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying the chemical structure of mithramycin through derivatization at specific positions (3 and 4 on ring C). This structural parameter modification changes the binding affinity and selectivity profile, transforming the compound from a broad-spectrum inhibitor (affecting both ETS and Sp factors) to a selective ETS inhibitor with reduced toxicity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If mithramycin analogues are developed to improve selectivity against Ewing sarcoma cells, then therapeutic index is improved, but structural complexity increases

Engineering Contradiction:

ImproveselectivityVSAvoidstructural complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by focusing modifications on specific segments of the mithramycin molecule (positions 3 and 4 on ring C) rather than attempting comprehensive structural changes. This targeted segmental modification approach achieves selectivity improvement while minimizing overall structural complexity and maintaining synthesis feasibility

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS11692003B2Mithramycin derivatives having increased selectivity and anti-cancer activity

Publication Date: 2023.07.04 UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION

AI summary

Mithramycin (MTM) short side chain ketone (SK) derivatives and MTM short side chain diketone (SDK) derivatives are provided. The MTM SK and MTM SDK derivatives are useful for treatment of cancer or neuro-diseases associated with an aberrant erythroblast transformation-specific transcription factor. Unique MTM SK and MTM SDK derivatives have increased selectively toward ETS transcription factor.