Irreversible USP7 Inhibitors Modulate Treg and Teff Cells

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Solution Overview

Problem

Current cancer treatments are inadequate in effectively targeting and inhibiting cancer cell growth and immune evasion mechanisms, particularly in modulating the activity of regulatory T cells (Treg) and effector T cells (Teff) within the tumor microenvironment.

Innovation Solution

Development of irreversible USP7 inhibitors that selectively target and inhibit the deubiquitinating enzyme USP7, reducing Treg cell activity and enhancing Teff cell activity, thereby inhibiting tumor growth and modulating the immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional cancer treatments are used, then general tumor treatment is provided, but they are inadequate in effectively targeting and inhibiting cancer cell growth and immune evasion mechanisms

Engineering Contradiction:

Improveeffectiveness of cancer treatmentVSAvoidability to target specific immune mechanisms

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the cancer treatment approach by specifically targeting the USP7 enzyme within the broader cancer therapy context. The azole compounds are designed to selectively inhibit USP7, which has specific substrates including Foxp3 in Treg cells, thereby providing targeted intervention rather than general cancer treatment

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality by designing compounds that specifically interact with the USP7 active site and its substrate binding pocket. The azole compounds exhibit selective inhibition of USP7 over other deubiquitinating enzymes, achieving localized and specific immunomodulatory effects in the tumor microenvironment

Inventive Principle:

Principle #3Local quality

2Duration of action of moving object

If irreversible USP7 inhibitors are used, then long duration of action is achieved after short exposure, but selective targeting of Treg cells versus Teff cells must be maintained

Engineering Contradiction:

Improveduration of USP7 inhibitionVSAvoidselectivity between Treg and Teff cell modulation

Core Design Contradiction:

Duration of action of moving objectVSMeasurement precision

Solution Approach 1:

The patent employs preliminary action by designing irreversible inhibitors that form covalent bonds with USP7, ensuring prolonged inhibition duration. The azole compounds are structurally pre-configured with electrophilic warheads that irreversibly modify the catalytic cysteine of USP7, providing sustained effect after brief exposure

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent utilizes parameter changes by modifying the chemical structure of azole compounds to optimize both binding affinity and selectivity. Structural variations in the azole core and substituent groups tune the compounds' ability to selectively inhibit USP7 while maintaining differential effects on Treg versus Teff cells

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11273154B2Azole compounds as ubiquitin-specific protease USP7 inhibitors

Publication Date: 2022.03.15 PROGENRA INC

AI summary

Method and compounds for treating cancer by, for example, modulating immune system activity, are provided.