Small Molecule EphA2 Agonist Inversion for Cancer Treatment

Solution Overview

Problem

EphA2 receptor has diametrically opposite roles in tumorigenesis, making it challenging to develop effective cancer treatments, as its overexpression is associated with both oncogenic and tumor suppressor functions, depending on ligand stimulation and cellular context.

Innovation Solution

Administration of a small molecule agonist of the EphA2 receptor protein, such as doxazosin, which activates and internalizes EphA2 receptors in cancer cells, inhibiting tumor growth and metastasis by severing pro-oncogenic Akt-EphA2 crosstalk and reactivating intrinsic ligand-dependent tumor suppressor functions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If EphA2 is overexpressed, then tumor suppressor function is enhanced, but oncogenic function is also promoted

Engineering Contradiction:

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies inversion by using an agonist that forces EphA2 into its tumor suppressor state through ligand-like binding, reversing the conventional approach of blocking EphA2. This activates the repulsive signaling pathway that inhibits migration and proliferation, while avoiding the pro-oncogenic effects of ligand-independent activation.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the functional state of EphA2 by introducing a small molecule agonist that mimics ephrin-A1 binding, thereby altering the signaling parameters from pro-oncogenic to tumor suppressor mode. This shifts the receptor's behavior from promoting migration to inhibiting it.

Inventive Principle:

Principle #35Parameter changes

2Speed

If ligand-independent EphA2 activation occurs, then cell migration is promoted, but tumor suppressor function is lost

Engineering Contradiction:

Core Design Contradiction:

SpeedVSReliability

Solution Approach 1:

The patent introduces a small molecule agonist as an intermediary that selectively activates the tumor suppressor pathway without triggering the pro-oncogenic effects. This mediator binds to EphA2 and activates repulsive signaling while avoiding the harmful ligand-independent activation that promotes migration.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If ephrin-A1 expression is reduced, then EphA2 overexpression is correlated with poor prognosis, but ligand-dependent signaling is compromised

Engineering Contradiction:

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent creates a synthetic copy of the ephrin-A1 ligand in the form of a small molecule agonist that binds to EphA2 and reproduces the tumor suppressor signaling effects. This copy functional replacement restores ligand-dependent signaling in tumors where endogenous ephrin-A1 is reduced or lost.

Inventive Principle:

Principle #26Copying

Data Source

PatentUS11814372B2Agonists of EPHA and their uses

Publication Date: 2023.11.14

AI summary

A method of treating cancer in a subject includes administering to the subject a therapeutically effective amount of a small molecule agonist of EphA2 receptor protein, the small molecule having a general formula: A-L-X-Z (I).