Bivalent Compounds for Selective CBP P300 Protein Degradation
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Solution Overview
Problem
Current therapeutic options are inadequate for effectively targeting cyclic-AMP response element binding protein (CBP) and/or adenoviral E1A binding protein of 300 kDa (P300), which are crucial in various biological processes but also implicated in diseases such as cancer and inflammatory conditions.
Innovation Solution
Development of bivalent compounds comprising a CBP/P300 ligand conjugated to a degradation tag, specifically binding to CBP/P300 proteins and utilizing ubiquitin ligases or hydrophobic groups to induce protein degradation, thereby modulating their activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If P300 and CBP are depleted to compromise tumor growth, then cancer treatment efficacy is improved, but immune cell functions are compromised
Solution Approach 1:
The bivalent compound incorporates a degradation tag that enables selective degradation of P300/CBP in specific cellular contexts. The compound consists of a P300/CBP ligand portion that binds to the target protein and a degradation tag portion that recruits ubiquitin ligases, creating localized degradation activity that spares immune cell functions while targeting cancer cells
Solution Approach 2:
The bivalent compound acts as an intermediary molecule that mediates between the P300/CBP target and the ubiquitin degradation system. By introducing this intermediary compound with dual functionality (binding + degradation tag), selective degradation is achieved without directly depleting P300/CBP in immune cells
2Reliability
If conventional P300/CBP inhibitors are used, then transcriptional activation is blocked, but protein stability is maintained leading to limited therapeutic effect
Solution Approach 1:
The invention merges two distinct functions into a single bivalent compound: (1) P300/CBP binding capability from known inhibitors, and (2) ubiquitin-mediated degradation signal from degradation tags. This combination allows simultaneous transcriptional blocking and protein destabilization, achieving enhanced therapeutic effect
Solution Approach 2:
The bivalent compound functions as a composite molecular entity combining a ligand portion (from conventional inhibitors like GNE-781 or CPD compounds) with a degradation tag portion (such as pomalidomide, thalidomide, or lenalidomide derivatives). This composite structure enables dual mechanism of action
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
The bivalent compounds effectively target and degrade CBP/P300 proteins, offering potential therapeutic benefits for treating cancer, inflammatory diseases, and other indications by modulating their activity.
Implementation Method 1
a CBP/P300 ligand conjugated to a degradation tag, wherein the CBP/P300 ligand binds to a CBP/P300 protein
Implementation Method 2
utilizing ubiquitin ligases or hydrophobic groups to induce protein degradation
Data Source
AI summary
Provided are bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and methods of use the bivalent compounds for the treatment of certain disease in a subject in need thereof, and methods for identifying such bivalent compounds.