BCL6-BRD4 TCIP1 (TCIP1) is a potent BCL6-BRD4 transcriptional/epigenetic chemical inducer of proximity (TCIP) by covalently linking BCL6 binder BI-3812 to BRD4 ligand JQ1, selectively kills DLBCL cells with EC50 of 1.3 nM against KARPAS422 cell.
TCIP1 rapidly and robustly killed other DLBCL lines with high levels of BCL6,  but JQ1 and BI3812 separately or together shows100–1,000-fold less-effective cell killing.
TCIP1 is 200–10,000-fold more potent in killing DLBCL cells than the degradation of BRD4 by dBET1 and/or degradation of BCL6 by BI3802.
TCIP1 induces a stable, cooperative protein-protein interaction between bromodomain 1 (BD1) of BRD4 and the BTB domain of BCL6.
TCIP1 shows affinity for intracellular ternary complex of BRD4 with Kd of 340 nM in TR-FRET assays.
TCIP1 induces G1/S and G2/M block in the cell cycle, TCIP1 (10 nM) represses MYC and its targets while activating pro-apoptotic genes in KARPAS422 cells.
TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription.