Design of Potent and Selective BCL6 Transcriptional Chemical Inducers of Proximity through Linker Optimization

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.