Piperazine-2,5-diones for TGF-beta Inhibition

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Solution Overview

Problem

Current anti-TGF-β therapeutics lack the ability to distinguish between homeostatic and disease-related TGF-β activity, leading to potential adverse effects, and existing peptides for altering TGF-β activity are costly, difficult to synthesize, and have short plasma stability.

Innovation Solution

Development of piperazine-2,5-diones compounds with specific structures that inhibit TGF-β activity, offering a more cost-effective and stable alternative for treating disorders associated with TGF-β dysregulation, including cancers and fibrotic conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing peptides are used to alter TGF-β activity, then TGF-β activity can be modulated, but the peptides are costly, difficult to synthesize, and have short plasma stability

Engineering Contradiction:

Improveplasma stabilityVSAvoidsynthesis difficulty

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the chemical parameters from peptide-based structures to piperazine-2,5-dione small molecule structures, fundamentally altering the molecular class to achieve improved plasma stability and easier synthesis while maintaining TGF-β modulation activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces expensive, difficult-to-synthesize peptides with cheaper, easier-to-manufacture small molecule compounds that have extended plasma half-life, effectively creating a more economical and stable therapeutic alternative

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Reliability

If current anti-TGF-β therapeutics are used, then TGF-β activity is inhibited, but there is no ability to distinguish between homeostatic and disease-related TGF-β activity leading to potential adverse effects

Engineering Contradiction:

Improvetherapeutic specificityVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds that selectively target and modulate abnormal TGF-β activation in diseased tissues while preserving normal homeostatic TGF-β signaling in healthy tissues, achieving spatial and functional specificity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of broadly inhibiting all TGF-β activity like current therapeutics, the patent inverts the approach by selectively modulating only the pathological activation pathways, thereby protecting homeostatic functions while treating disease

Inventive Principle:

Principle #13The other way round (Inversion)

3Duration of action of moving object

If peptides are used for TGF-β modulation, then TGF-β activity can be altered, but the peptides have short plasma stability half-life

Engineering Contradiction:

Improveplasma stability half-lifeVSAvoidsynthesis cost

Core Design Contradiction:

Duration of action of moving objectVSEase of manufacture

Solution Approach 1:

The patent fundamentally changes the molecular parameters from large peptide molecules to small piperazine-2,5-dione molecules, resulting in dramatically improved plasma stability half-life and reduced synthesis costs while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11505531B2Piperazine-2,5-diones as TGF-beta inhibitors

Publication Date: 2022.11.22 THE UAB RESEARCH FOUNDATION INC

AI summary

The present disclosure is concerned with piperazine-2,5-diones that are capable of inhibiting TGF-β and methods of treating cancers such as, for example, multiple myeloma and a hematologic malignancy, and methods of treating fibrotic conditions using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.