ID2 Protein Phosphorylation for HIFα Degradation

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Solution Overview

Problem

Current treatments for tumors and cancers involving ID proteins, such as ID2 and HIFα, lack effective mechanisms to regulate their activity, particularly in relation to phosphorylation and degradation, which are crucial for controlling tumor angiogenesis and glioma sternness.

Innovation Solution

Regulating the activity of ID2 protein through phosphorylation of Thr 27 by DYRK1 kinase, which affects HIFα stability and degradation, using compositions and methods that increase DYRK1 expression or activity to accelerate HIFα degradation in cancer cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If ID2 protein activity is increased to promote tumor angiogenesis and stemness, then tumor growth and progression are enhanced, but therapeutic control and treatment efficacy are reduced

Engineering Contradiction:

Improvetumor growth rateVSAvoidtherapeutic control

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the phosphorylation state of ID2 at Thr 27 from unphosphorylated to phosphorylated, which fundamentally alters ID2's binding affinity to VHL and its subsequent degradation rate. This parameter change (phosphorylation status) allows precise control of ID2 activity levels, enabling therapeutic regulation of tumor angiogenesis and stemness while maintaining controllability through DYRK1 modulation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent establishes a feedback mechanism where DYRK1 phosphorylation of ID2 creates a regulatory loop that controls ID2 stability. The phosphorylated ID2 is degraded by VHL, reducing its pro-tumorigenic effects, while the phosphorylation event itself is regulated by DYRK1 activity. This feedback system provides therapeutic control by allowing modulation of the phosphorylation-degradation cycle to achieve desired tumor growth inhibition

Inventive Principle:

Principle #23Feedback

2Stability of the object's composition

If HIFα protein stability is increased to enhance hypoxia response and tumor adaptation, then tumor survival under hypoxia is improved, but tumor angiogenesis control and treatment response are worsened

Engineering Contradiction:

ImproveHIFα protein stabilityVSAvoidtumor angiogenesis

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent introduces phosphorylated ID2 as an intermediary that mediates between DYRK1 kinase activity and HIFα degradation. Phosphorylated ID2 binds to VHL, facilitating HIFα ubiquitination and degradation. This intermediary mechanism allows indirect control of HIFα stability through ID2 phosphorylation, providing a therapeutic target that regulates tumor angiogenesis without directly targeting HIFα itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs preliminary phosphorylation of ID2 by DYRK1 before ID2 can bind to and stabilize HIFα. By establishing the phosphorylated state of ID2 in advance, the system pre-configures the degradation pathway for HIFα, preventing HIFα accumulation and subsequent pro-angiogenic gene expression before they can occur

Inventive Principle:

Principle #10Preliminary action

3Object-affected harmful factors

If ID2 phosphorylation at Thr 27 is increased to accelerate HIFα degradation, then tumor angiogenesis is inhibited, but the complexity of the regulatory pathway increases

Engineering Contradiction:

Improvetumor angiogenesisVSAvoidregulatory pathway complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent demonstrates that DYRK1 kinase performs multiple functions: it phosphorylates ID2 at Thr 27, and this single phosphorylation event simultaneously controls ID2's binding to VHL, ID2's degradation rate, and consequently HIFα stability. This multi-functionality reduces regulatory complexity by having one kinase (DYRK1) control multiple aspects of the ID2-HIFα axis through a single phosphorylation site

Inventive Principle:

Principle #6Universality (Multi-functionality)

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

This approach effectively decreases HIFα half-life and stability in cancer cells, potentially inhibiting tumor growth and improving treatment outcomes by targeting key regulatory pathways in ID protein-related diseases.

Implementation Method 1

Regulating the activity of ID2 protein through phosphorylation of Thr 27 by DYRK1 kinase

Methodology Applied

Scientific EffectPhosphorylation:

Implementation Method 2

Mutation of the VHL gene hinders the negative control of HIFα protein stability through the ubiquitin ligase activity of VHL

Methodology Applied

Scientific EffectProteasomal degradation:

Data Source

PatentEP3400003B1Compositions for regulating activity of inhibitor of DNA binding-2 (ID2) protein

Publication Date: 2023.05.03 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

Figure 1A~1B
Figure 2A
Figure 2B

AI summary

The present disclosure provides, in one embodiment, a method of treating or preventing an ID2 protein-related disease in a patient at risk of developing or having such a disease by administering to the patient a composition in an amount and for a time sufficient to increase degradation of HIFα in a cell affected by the ID2 protein-related disease in the patent and/or to decrease half-life of HIFα in the cell affected by the ID2 protein-related disease in the patient, as compared to an untreated cell affected by the ID2 protein-related disease.