MUC1-Caspase-8 Interaction Modulation for Apoptosis Control

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Solution Overview

Problem

MUC1 inhibits apoptosis in cancer cells by blocking the activation of caspase-8 and interfering with the death-inducing signaling complex, making it challenging to treat cancers and inflammatory conditions effectively.

Innovation Solution

Modulating the interactions between MUC1 and caspase-8, or MUC1 and FADD, by identifying and designing compounds that inhibit or enhance these interactions, which can be used to treat various pathological conditions characterized by elevated or decreased levels of apoptosis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If MUC1 blocks activation of caspase-8 and apoptosis in cancer cells, then cancer cell survival is improved, but apoptosis resistance increases making cancer treatment more difficult

Engineering Contradiction:

Improvecancer cell survivalVSAvoidapoptosis resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses FADD as an intermediary protein that bridges death receptor signaling to caspase-8 activation. By targeting the FADD-MUC1-caspase-8 interaction complex, the invention disrupts the apoptotic pathway without directly affecting MUC1 or caspase-8 individually, enabling selective modulation of apoptosis resistance in cancer cells

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention modifies the interaction parameters between MUC1 and caspase-8 through small molecule compounds that change the binding affinity and interaction dynamics. This allows shifting the equilibrium between pro-apoptotic and anti-apoptotic states, thereby overcoming cancer cell apoptosis resistance

Inventive Principle:

Principle #35Parameter changes

2Reliability

If MUC1 interacts with and competes for binding to FADD, then caspase-8 recruitment to DISC is inhibited, but death receptor signaling is blocked

Engineering Contradiction:

Improveapoptosis inhibitionVSAvoiddeath receptor signaling blockage

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces FADD as a critical intermediary that mediates between death receptor ligands and caspase-8. By targeting the FADD binding interface, the invention creates a selective disruption point that prevents caspase-8 recruitment without completely blocking death receptor signaling, allowing for controlled modulation of apoptotic pathways

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention segments the death receptor signaling pathway into distinct functional modules: death receptor ligands, FADD adapter, MUC1 inhibitor, and caspase-8 executor. This segmentation allows selective targeting of specific interaction points, enabling independent modulation of signaling strength and apoptosis execution

Inventive Principle:

Principle #1Segmentation

3Reliability

If compounds modulate MUC1-caspase-8 interactions to treat cancer, then cancer therapy effectiveness is improved, but compound identification and development complexity increases

Engineering Contradiction:

Improvecancer therapy effectivenessVSAvoidcompound identification complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses FADD as a measurable intermediary marker to screen for active compounds. By detecting changes in FADD binding or interaction status, the system provides a straightforward readout for compound efficacy, simplifying the high-throughput screening process while maintaining therapeutic relevance

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention replaces complex cellular apoptosis assays with simplified biochemical binding assays that detect MUC1-caspase-8 or FADD-MUC1 interactions directly. This substitution of measurement approaches reduces experimental complexity while maintaining therapeutic validation

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

4Object-affected harmful factors

If MUC1 pathway is inhibited to treat inflammatory conditions, then inflammation control is improved, but apoptosis regulation in immune cells is affected

Engineering Contradiction:

Improveinflammation controlVSAvoidapoptosis regulation

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies local quality by targeting specific interaction interfaces (MUC1-FADD or MUC1-caspase-8) rather than broadly inhibiting the entire apoptosis pathway. This localized targeting allows differential regulation of apoptosis in different cell types, preserving necessary immune cell apoptosis while reducing harmful inflammation-driven apoptosis

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS8809002B2MUC1, caspase-8, and DED-containing proteins

Publication Date: 2014.08.19 DANA FARBER CANCER INSTITUTE INC

AI summary

The disclosure features a variety of compositions and methods for modulating an interaction between MUC1 and caspase-8 and/or an interaction between MUC1 and a DED-containing protein (e.g., an anti-apoptotic DED-containing protein or a pro-apoptotic DED-containing protein). Such methods and compositions are useful for the treatment or prevention of e.g., a variety of pathological disorders characterized by elevated or decreased levels of apoptosis. Moreover, the compositions and methods are also useful to identify, design, and generate compounds that modulate the interactions. The compounds and/or pharmaceutical compositions containing the compounds can be used in the treatment of disease.