Peptidomimetic Macrocycles for p53 Reactivation in Solid Tumors

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Solution Overview

Problem

Current methods lack effective solutions for treating solid tumors with p53 deactivating mutations, as p53 is crucial for preventing malignant transformation, and existing treatments are inadequate for tumors with wild-type or mutated p53 proteins.

Innovation Solution

Administration of peptidomimetic macrocycles that bind to MDM2 and/or MDMX proteins to disrupt interactions with p53, thereby modulating p53 activity and treating solid tumors with various p53 mutations or expressions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for solid tumors, then general tumor treatment is attempted, but they are ineffective for tumors with p53 deactivating mutations or overexpressed MDM2/MDMX

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidapplicability to different p53 mutation types

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs peptidomimetic macrocycles with modified structural parameters compared to natural p53 peptides. These macrocyclic structures exhibit enhanced binding affinity and selectivity for MDM2 and MDMX, allowing effective treatment across multiple tumor types with different p53 mutation statuses including wild-type, mutated, and overexpressed conditions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The peptidomimetic macrocycle acts as an intermediary molecule that binds to MDM2/MDMX proteins and disrupts their interaction with p53. This mediator approach restores p53 function indirectly by preventing its degradation, thereby treating tumors regardless of whether p53 mutations are present or absent

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If p53 is targeted directly, then tumors with wild-type p53 may be treated, but tumors with p53 deactivating mutations cannot be effectively treated

Engineering Contradiction:

Improvetreatment effectiveness for wild-type p53 tumorsVSAvoidtreatment coverage for mutated p53 tumors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of directly targeting p53 (which is ineffective in mutated tumors), the patent inverts the approach by targeting MDM2/MDMX, the negative regulators of p53. By inhibiting these regulators, the treatment indirectly restores p53 function in wild-type tumors and induces apoptosis in mutated tumors through alternative pathways

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The peptidomimetic macrocycle serves as an intermediary that modulates the MDM2/p53 and MDMX/p53 interactions. This indirect mechanism allows the treatment to be effective across different p53 mutation types by restoring p53 activity where possible and triggering apoptosis through the disrupted regulatory pathway

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS10471120B2Peptidomimetic macrocycles and uses thereof

Publication Date: 2019.11.12 AILERON THERAPEUTICS INC

AI summary

Methods for treating solid tumor, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a solid tumor, determined to lack a p53 deactivation mutation, in a subject.