Carboline Derivatives Inhibit VEGF Translation via 5'-UTR Binding

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Aberrant angiogenesis, driven by excessive VEGF production, contributes to various diseases such as cancer, diabetic retinopathy, and chronic inflammation, for which there is a need to inhibit VEGF translation effectively to reduce angiogenesis and treat associated pathologies.

Innovation Solution

Development and administration of VEGF translation-inhibiting compounds, specifically carboline derivatives, that target the 5′-UTR-dependent translation of VEGF, reducing its production in cells and tissues, thereby inhibiting angiogenesis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If VEGF translation is inhibited using conventional methods, then angiogenesis is reduced, but the inhibition efficiency is insufficient due to lack of specificity

Engineering Contradiction:

ImproveVEGF translation inhibition efficiencyVSAvoiddrug development complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the molecular parameters of the inhibitor by developing carboline derivatives with specific structural features (substituents at positions 1, 9, and methylene bridge configurations) to achieve nanomolar to sub-nanomolar inhibition potency against VEGF translation while maintaining selectivity for the VEGF 5'-UTR IRES element

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention applies local quality by designing inhibitors that specifically target the 5'-UTR region of VEGF mRNA containing the IRES element, rather than affecting VEGF at multiple sites. The carboline derivatives are structured to bind specifically to this local region, achieving selective inhibition of VEGF translation without affecting other cellular processes

Inventive Principle:

Principle #3Local quality

2Reliability

If VEGF levels are reduced to treat diseases, then therapeutic efficacy is improved, but off-target effects may occur

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses the 5'-UTR IRES element of VEGF mRNA as an intermediary target. The carboline derivatives bind to this specific intermediary structure rather than directly to the VEGF protein or general translation machinery, enabling selective inhibition of VEGF translation while sparing other cellular functions and reducing off-target effects

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If small molecules are developed to inhibit VEGF translation, then drug potency is increased, but the complexity of identifying and optimizing compounds increases

Engineering Contradiction:

Improveinhibition potencyVSAvoidcompound identification and optimization process

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent segments the VEGF mRNA structure by specifically targeting the 5'-UTR region containing the IRES element, separate from the coding region and 3'-UTR. This segmentation allows for the development of inhibitors that act at a specific location on the mRNA, simplifying the identification and optimization process by focusing on a discrete target structure rather than the entire mRNA molecule

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS8076353B2Inhibition of VEGF translation

Publication Date: 2011.12.13 PTC THERAPEUTICS INC

AI summary

In accordance with the present invention, methods for inhibiting the translation of VEGF and methods for decreasing VEGF level by inhibiting VEGF translation are provided. In another aspect of the invention, compounds that inhibit the 5′-UTR-dependent translation of VEGF and methods for identifying such compounds are provided.