BCL6 BTB-Domain Inhibitors for Selective Corepressor Blocking
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need to develop agents that inhibit the tumorigenic effects of BCL6, a zinc finger transcription repressor implicated 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 pharmaceutically acceptable salts, hydrates, or solvates thereof, which can be administered to inhibit BCL6 activity in cells and treat proliferative disorders such as cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If BCL6 is upregulated to drive B cell proliferation and antibody production, then immune response diversity is improved, but malignant B cell proliferation occurs leading to lymphoma
Solution Approach 1:
The patent introduces small molecule compounds as intermediary agents that selectively bind to the BCL6 BTB domain, acting as a mediator to block the interaction between BCL6 and its corepressor proteins (SMRT, NCoR, BCoR). This intermediary action prevents BCL6-mediated transcriptional repression without directly affecting B cell proliferation mechanisms, thereby suppressing malignant growth while preserving normal immune function.
Solution Approach 2:
The invention changes the molecular binding parameters by designing compounds with specific structural features ( Formula I) that optimize affinity for the BCL6 BTB domain while maintaining selectivity. By modifying chemical parameters such as molecular weight, lipophilicity, and binding kinetics, the compounds achieve effective BCL6 inhibition with appropriate pharmacological properties for therapeutic use.
2Stability of the object's composition
If BCL6 recruits corepressor proteins to repress gene expression, then B cell proliferation is controlled, but tumourigenic effects are enhanced
Solution Approach 1:
The patent extracts the BTB domain as the critical functional element of BCL6 responsible for corepressor recruitment. By designing compounds that specifically target and bind to this extracted domain, the invention disrupts the BCL6-corepressor interaction without affecting other BCL6 functions, thereby selectively eliminating tumourigenic effects while preserving essential gene expression control mechanisms.
3Reliability
If selective BCL6 inhibitors are developed to prevent corepressor recruitment, then malignant proliferation is inhibited, but drug specificity and selectivity must be maintained to avoid off-target effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features at particular molecular positions (as defined in Formula I with specific R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 substituents). These localized structural modifications optimize binding affinity for the BCL6 BTB domain while maintaining selectivity, ensuring reliable inhibition without compromising molecular specificity.
Data Source
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.