EP300/CBP Degrader Compounds for MYC Transcriptional Silencing

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Solution Overview

Problem

Current pharmacologic inhibition strategies for MYC-driven cancers, such as neuroblastoma, are insufficient to drive tumor regression in vivo, and there is a need for an alternative approach to target EP300 and CBP for effective cancer treatment.

Innovation Solution

Development of bispecific compounds that bind to histone acetyltransferases p300 and CBP, utilizing a targeting ligand and a degron to recruit the Ubiquitin/Proteasome System for selective degradation of these proteins, thereby inhibiting their activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If transcriptional inhibition is used to target MYC-driven cancers, then transcriptional collapse and apoptosis are achieved in vitro, but tumor regression is insufficient in vivo

Engineering Contradiction:

Improvetumor regression efficacyVSAvoidtranscriptional inhibition effectiveness

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

Instead of inhibiting transcriptional activity, the invention inverts the approach by promoting transcriptional elongation through BRD4 inhibition, which disrupts the transcriptional machinery's ability to function properly, leading to more effective tumor regression in vivo while maintaining the transcriptional collapse effect observed in vitro

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If small molecule inhibitors are used to inhibit EP300/CBP activity, then transcriptional regulation is disrupted, but high concentrations are required to achieve effective degradation

Engineering Contradiction:

Improveprotein degradation efficacyVSAvoidinhibitor concentration

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The invention introduces an intermediary mechanism where BRD4 acts as a mediator between the small molecule inhibitor and EP300/CBP. The inhibitor binds to BRD4, forming a ternary complex that brings the inhibitor into proximity with EP300/CBP, enabling effective protein degradation at lower concentrations than direct inhibition would require

Inventive Principle:

Principle #24Intermediary (Mediator)

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 bispecific compounds effectively degrade EP300 and CBP, leading to transcriptional silencing of MYC expression and potential tumor regression, with lower required concentrations compared to traditional small molecule inhibitors.

Implementation Method 1

utilizing a targeting ligand and a degron to recruit the Ubiquitin/Proteasome System for selective degradation of these proteins

Methodology Applied

Scientific EffectUbiquitin/Proteasome System:

Data Source

PatentUS12496348B2Small molecule target bromo/acetyl proteins and uses thereof

Publication Date: 2025.12.16 DANA FARBER CANCER INSTITUTE INC

AI summary

Disclosed are bispecific compounds (degraders) that target EP300/CBP for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat disease.