Abstract 3981: A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death

Abstract Cancer therapies that activate cell death are critical to avoid relapse. Approximately 30% of diffuse large B cell lymphoma (DLBCL) cases, the most common non-Hodgkin lymphoma, fail standard-of-care treatment regimens, highlighting the need for new death-promoting targeted therapies. Here, we introduce a gain-of-function small molecule modality that kills DLBCL cells at sub-nanomolar potency (IC50 = 0.8 nM) through induced proximity. These bivalent compounds, Lysine Acetyltransferase Transcriptional/Epigenetic Chemical Inducers of Proximity (KAT-TCIPs), leverage the endogenous activity of the co-activating KATs E1A Binding Protein p300 (p300) and CREB-Binding Protein (CBP) to drive the transcription of death-promoting genes normally repressed by oncogenes. Specifically, KAT-TCIPs recruit p300/CBP to genomic loci controlled by the master transcriptional repressor BCL6, dysregulated in ∼40% of DLBCL cases, and rapidly reprogram the epigenome to promote BCL6-dependent cell cycle arrest and apoptosis. We report the first X-ray co-crystal structure of a TCIP molecule bound to p300 and BCL6, which guided the optimization of our lead KAT-TCIP, TCIP3. Additional biophysical characterization of TCIP3 revealed its function as a molecular glue that cooperatively seeds ternary complexes on chromatin. This compound exhibits robust preclinical efficacy in vivo. It ablates germinal center B cells, which are naturally enriched for BCL6 expression, in immunized mice (5 mpk bid dosed intraperitoneally) relative to vehicle controls. Additionally, TCIP3 eliminates tumors in DLBCL cell line-derived xenograft models within 11 days at the same dose. Notably, this molecule spares healthy lymphocytes and fibroblasts in cytotoxicity analyses. Collectively, our findings establish KAT-TCIPs as powerful tools for co-opting the malignant function of oncogenic drivers to activate robust cell death, with implications for precision epigenetic therapies. Citation Format: Meredith Nicole Nix, Sai Gourisankar, Sabin Nettles, Kevin Bowman, Haopeng Yang, Brendan G. Dwyer, Roman C. Sarott, Hind Abuzaid, Michael Martinez, Andrey Krokhotin, Lei Chen, Mark M. Davis, Daniel Fernandez, Tinghu Zhang, Michael R. Green, Stephen M. Hinshaw, Nathanael S. Gray, Gerald R. Crabtree. A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3981.