Dynasore Inhibitor Enhances TGF-beta Signaling

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for conditions characterized by decreased TGF-β signaling, such as inflammatory conditions, cancer, and cardiovascular diseases, are limited in enhancing TGF-β responsiveness effectively.

Innovation Solution

The use of clathrin-dependent endocytosis inhibitors, specifically dynasore, which enhances TGF-β signaling by inhibiting dynamin GTPase activity, thereby promoting TGF-β-stimulated Smad2 phosphorylation and nuclear localization, and is combined with a statin for therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If clathrin-dependent endocytosis inhibitors are used, then TGF-β signaling is enhanced, but cellular uptake of TGF-β may be reduced

Engineering Contradiction:

ImproveTGF-β signaling effectivenessVSAvoidcellular uptake of TGF-β

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent uses clathrin-dependent endocytosis inhibitors as intermediaries that indirectly enhance TGF-β signaling by preventing receptor internalization, rather than directly increasing TGF-β uptake. The inhibitors mediate the effect by blocking the degradation pathway, allowing sustained receptor activation without requiring increased cellular uptake of the cytokine itself.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

Instead of trying to increase TGF-β uptake to enhance signaling, the patent inverts the approach by blocking the endocytosis pathway that would normally remove active receptors from the cell surface. This inverse strategy maintains higher levels of active signaling complexes without needing to increase initial uptake.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If dynasore is administered to enhance TGF-β signaling, then conditions like atherosclerosis are ameliorated, but off-target effects may occur

Engineering Contradiction:

Improvetherapeutic efficacy for atherosclerosisVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent optimizes the concentration and administration parameters of dynasore to achieve therapeutic efficacy while minimizing off-target effects. By carefully controlling the dosage parameters, the treatment enhances TGF-β signaling in vascular cells without causing excessive disruption to other cellular processes that rely on endocytosis.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Dynasore effectively enhances TGF-β signaling, ameliorating conditions like atherosclerosis by counteracting suppressed TGF-β responsiveness, and when combined with a statin, offers a therapeutic approach for treating various diseases characterized by decreased TGF-β signaling.

Implementation Method 1

clathrin-dependent endocytosis inhibitors, specifically dynasore, which enhances TGF-β signaling by inhibiting dynamin GTPase activity

Methodology Applied

Scientific EffectDynamin GTPase activity inhibition:

Implementation Method 2

enhances TGF-β-stimulated Smad2 phosphorylation and nuclear localization

Methodology Applied

Scientific EffectPhosphorylation:

Data Source

PatentEP2341913B1Method of enhancing TGF-beta signalling

Publication Date: 2014.11.19 AUXAGEN

Figure 1A(a)~1A(b)
Figure 1B(a)~1D(b)
Figure 1E~1H

AI summary

The present invention is directed to a method of enhancing TGF-ß signaling in a subject comprising administering to said subject a clathrin-dependent endocytosis inhibitor in an amount sufficient to enhance TGF- ß signaling. In another aspect, the invention is directed to a method of treating a condition associated with decreased TGF- ß signaling in a patient in need thereof comprising administering to said patient a clathrin-dependent endocytosis inhibitor in a therapeutically effective amount.