GIT1 Inhibitors Block VEGFR-Notch1-DLL4 Signaling

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Solution Overview

Problem

Current therapies lack effective agents to modulate angiogenesis, particularly in conditions like tumor growth, macular degeneration, and pulmonary arterial hypertension, as existing treatments fail to adequately control abnormal angiogenesis.

Innovation Solution

Development of GIT1 inhibitors, specifically peptides derived from the ankyrin repeat domain and spa2 homology domain of GIT1, which interfere with the VEGFR-Notch1-Delta like 4 signaling pathway to inhibit angiogenesis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing therapies are used to treat abnormal angiogenesis, then treatment is provided, but the therapies fail to adequately control abnormal angiogenesis in conditions like tumor growth, macular degeneration, and pulmonary arterial hypertension

Engineering Contradiction:

Improveefficacy of angiogenesis controlVSAvoidapplicability to multiple disease states

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces GIT1 inhibitors as intermediary agents that block the VEGF signaling pathway. GIT1 (G-protein coupled receptor kinase 1 interacting protein) serves as a mediator that interferes with the interaction between VEGF and its receptor, thereby inhibiting downstream signaling cascades including PLCγ activation, endothelial cell proliferation, migration, and tube formation. This intermediary approach provides reliable control across multiple disease states by targeting the common upstream pathway.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs parameter changes by modifying the signaling pathway activation state through GIT1 inhibition. Specifically, it reduces PLCγ activation levels, decreases endothelial cell proliferation rates, and inhibits tube formation capacity. These parameter changes in the biological system achieve adequate control of abnormal angiogenesis across various disease conditions.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If VEGF mediated PLCγ activation is blocked to inhibit angiogenesis, then abnormal angiogenesis is controlled, but endothelial cell migration, proliferation and tube formation are impaired

Engineering Contradiction:

Improvecontrol of abnormal angiogenesisVSAvoidimpairment of endothelial cell function

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the harmful overactive angiogenesis into a beneficial controlled state by using GIT1 inhibitors. The same VEGF signaling pathway that causes harmful abnormal angiogenesis in diseases like cancer and macular degeneration is targeted, and its inhibition produces beneficial therapeutic effects. The 'harm' of pathway activation is transformed into the 'benefit' of pathway suppression for therapeutic purposes.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS9670259B2Method of inhibiting angiogenesis using inhibitors of G-protein-coupled receptor kinase interacting protein-1 (GIT1)

Publication Date: 2017.06.06 UNIVERSITY OF ROCHESTER

AI summary

The present invention is directed to methods and compositions comprising G-protein-coupled receptor kinase interacting protein-1 (GIT1) inhibitors that are suitable for inhibiting angiogenesis in a subject and treating related conditions.