BCL6 BTB-Domain Inhibitors for Blocking Corepressor Recruitment

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Solution Overview

Problem

There is a need for agents that inhibit the tumorigenic effects of BCL6, a zinc finger transcription repressor involved in malignant B cell proliferation, by selectively binding to the BTB domain and preventing corepressor recruitment or inducing protein degradation.

Innovation Solution

Development of compounds that function as inhibitors of BCL6 activity, including pharmaceutical compositions comprising these compounds, which can be administered to inhibit BCL6 activity in cells and treat proliferative disorders such as cancer.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If BCL6 activity is inhibited by binding to the BTB domain, then malignant B cell proliferation is arrested, but selective binding and prevention of corepressor recruitment becomes difficult

Engineering Contradiction:

Improveinhibition of malignant B cell proliferationVSAvoidselective binding to BTB domain

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The compound is designed to interact specifically with the BTB domain of BCL6 through localized molecular features. The chemical structure includes specific functional groups and spatial arrangements that target the extended groove motif formed at the dimer interface of the BTB domain, enabling selective binding without affecting other regions of the protein.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The compound acts as an intermediary molecule that bridges the BTB domain and the corepressor proteins (SMRT, NCoR, BCoR). By binding to the extended groove motif, the compound physically blocks the recruitment of these corepressors, thereby inhibiting BCL6's transcriptional repressor function without requiring direct interaction with the corepressors themselves.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If compounds are designed to bind to the extended groove motif of the BTB domain, then corepressor recruitment is prevented, but manufacturing and synthesis complexity increases

Engineering Contradiction:

Improveprevention of corepressor recruitmentVSAvoidcompound synthesis

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The compound structure is divided into distinct functional segments: a core scaffold that targets the BTB domain binding site, and substituent groups that enhance affinity and selectivity. This modular design allows for systematic synthesis and optimization, where each segment can be independently modified to improve binding while maintaining manufacturability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The compound series includes variations in chemical parameters such as substituent types, molecular weight, and structural flexibility. These parameter changes allow optimization of binding affinity to the extended groove motif while balancing synthetic accessibility and manufacturing feasibility through iterative structure-activity relationship studies.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260042776A1BCL6 inhibitors

Publication Date: 2026.02.12 CANCER RESEARCH TECHNOLOGY LTD

AI summary

The present invention relates to compounds of formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity:wherein X1, X2, R1, R2, R30, R31 and Ring A are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.