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Design of Potent and Selective BCL6 Transcriptional Chemical Inducers of Proximity through Linker Optimization
Fang-Chi Chang1, Veronika M Shoba1, Oleh Shyshlyk2,3
1General Proximity Corporation, San Francisco, California 94107, United States.
Abstract:
B-cell lymphoma 6 (BCL6) is a transcriptional repressor implicated in diffuse large B-cell lymphoma and other malignancies. Conventional BCL6 inhibitors and degraders rely on loss-of-function mechanisms that may be limited by incomplete pathway suppression. Transcriptional chemical inducers of proximity (TCIPs) provide a gain-of-function alternative by redirecting transcriptional coactivators to BCL6-bound genomic loci, thereby reactivating pro-apoptotic gene expression. Here, we describe the medicinal chemistry optimization of BCL6 TCIPs through systematic linker engineering. A focused library of 66 heterobifunctional analogues derived from JQ1 and BI-3812 was evaluated for ternary complex formation, cellular potency, and selectivity. Linker rigidification and incorporation of cyclic elements significantly improved cellular selectivity, enhanced solubility, and increased the plasma exposure in mice. Computational analyses, competition experiments, and RNA sequencing indicate that the effects of the optimized analogues are driven by ternary complex formation. Together, these findings establish the linker architecture as a critical determinant of TCIP performance.
Insights
This study optimized B-cell lymphoma 6 (BCL6) transcriptional chemical inducers of proximity (TCIPs) by engineering linkers. Optimized TCIPs show improved selectivity and efficacy, offering a new therapeutic strategy for BCL6-driven cancers.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- B-cell lymphoma 6 (BCL6) is a key transcriptional repressor in various malignancies, including diffuse large B-cell lymphoma.
- Conventional BCL6 inhibitors have limitations due to incomplete pathway suppression.
- Transcriptional chemical inducers of proximity (TCIPs) offer a gain-of-function approach by reactivating pro-apoptotic gene expression.
Purpose of the Study:
- To optimize BCL6 TCIPs through systematic medicinal chemistry efforts focused on linker engineering.
- To enhance cellular potency, selectivity, solubility, and in vivo pharmacokinetic properties of BCL6 TCIPs.
Main Methods:
- Synthesis and evaluation of a focused library of 66 heterobifunctional BCL6 TCIP analogues derived from JQ1 and BI-3812.
- Assessment of ternary complex formation, cellular potency, and selectivity.
- Inclusion of computational analyses, competition experiments, and RNA sequencing to elucidate mechanism of action.
Main Results:
- Linker rigidification and the incorporation of cyclic elements significantly improved cellular selectivity and solubility.
- Optimized analogues demonstrated enhanced plasma exposure in mouse models.
- Evidence suggests that ternary complex formation is the primary driver of the observed therapeutic effects.
Conclusions:
- Medicinal chemistry optimization, particularly linker architecture, is critical for developing effective BCL6 TCIPs.
- The optimized TCIPs represent a promising gain-of-function strategy for targeting BCL6-driven cancers.
- This work establishes a foundation for the rational design of next-generation TCIPs.
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