Intermediate Filament Tetramerization Inhibition for Metastasis Control

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Solution Overview

Problem

Current anti-cancer therapies do not target intermediate filaments (IFs), which are crucial for cancer metastasis and over-expressed in various cancers, and there is a lack of understanding of the biochemical determinants of IF assembly at atomic resolution.

Innovation Solution

Inhibiting the interaction between the anchoring knob domain of an intermediate filament dimer and the hydrophobic pocket of another dimer using inhibitors such as peptides or CRISPR/Cas9 to disrupt tetramerization, specifically targeting vimentin or keratin heterodimers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current anti-cancer therapies are used, then cancer treatment is provided, but intermediate filaments are not targeted and cancer metastasis continues

Engineering Contradiction:

Improvecancer treatment effectivenessVSAvoidtherapeutic target coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention segments the intermediate filament assembly process into discrete targetable steps, specifically focusing on the tetramerization step. By identifying and targeting the specific molecular interface between dimers during tetramer formation, the therapy can selectively disrupt IF assembly without affecting other cellular processes, thereby improving treatment effectiveness while adding a new therapeutic dimension for metastasis prevention

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention introduces small molecule compounds as intermediary agents that bind to specific residues (such as F314, L318 in keratin 1 or F233, L237 in vimentin) to block the dimer-dimer interaction interface. These intermediary compounds prevent the formation of tetramers by occupying the binding site, thereby disrupting the entire IF assembly pathway and addressing the lack of therapeutic target coverage in current cancer treatments

Inventive Principle:

Principle #24Intermediary (Mediator)

2Loss of information

If understanding of IF assembly is increased at atomic resolution, then biochemical determinants are identified, but this knowledge gap currently prevents targeted inhibition

Engineering Contradiction:

Improvebiochemical knowledge of IF assemblyVSAvoiddevelopment of inhibitors

Core Design Contradiction:

Loss of informationVSEase of manufacture

Solution Approach 1:

The invention performs preliminary structural analysis and identification of key residues involved in dimer-dimer interactions before developing inhibitors. By using x-ray crystallography and biochemical studies to map the atomic-resolution structure of the tetramerization interface, the necessary biochemical information is obtained in advance, which then guides the rational design and development of targeted small molecule inhibitors

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention changes the parameter of structural resolution from general to atomic level by employing high-resolution x-ray crystallography and site-directed mutagenesis. This parameter change reveals specific atomic interactions (hydrogen bonds, hydrophobic interactions, salt bridges) at the dimer interface, providing the detailed biochemical determinants needed to design precise inhibitors that can block tetramerization

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If IFs are disrupted to prevent cancer metastasis, then novel therapeutic approach is achieved, but IF assembly process must be successfully inhibited

Engineering Contradiction:

Improvetherapeutic approachVSAvoidIF assembly inhibition

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The invention creates simplified models and analogs of the dimer-dimer interface to test and validate inhibitor mechanisms. By studying model systems and using computational modeling to replicate the key interactions, the reliability of IF assembly inhibition can be predicted and optimized before clinical application, enabling a versatile therapeutic approach with proven effectiveness

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The invention replaces the complex mechanical process of intermediate filament assembly with a targeted chemical intervention. Instead of attempting to disrupt the entire mechanical assembly process of IFs, small molecule compounds are used to chemically block the specific molecular recognition events at the dimer interface, substituting a simple chemical binding event for a complex mechanical assembly process and thereby ensuring reliable inhibition

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

Disruption of IF assembly impedes cancer metastasis by preventing tetramer formation, offering a novel therapeutic approach for cancers associated with IF over-expression.

Implementation Method 1

the interaction between the anchoring knob domain of a first intermediate filament dimer and the hydrophobic pocket of a second intermediate filament dimer

Methodology Applied

Scientific EffectHydrophobic interaction: Hydrophobe

Data Source

PatentUS12570973B2Compositions and methods for inhibiting intermediate filament tetramerization

Publication Date: 2026.03.10 YALE UNIVERSITY

AI summary

The present invention provides compositions and methods for inhibiting intermediate filament tetramerization and formation.