Abstract PO-012: Gain-of-function small molecules to reprogram oncogenic transcription in lymphoma

Abstract Conventional pharmacotherapy in oncology centers on target-centric silencing of aberrant protein function through small molecule inhibitors, degraders, or CRISPR/RNAi. In contrast, here we leverage induced proximity to develop pharmacology that activates dominant signaling pathways for a therapeutic effect. To develop this concept, we describe a new class of bivalent small molecules that reprogram cancer-driving gene expression to activate cell death signaling in diffuse large B cell lymphomas (DLBCL). These molecules, called Transcriptional Chemical Inducers of Proximity (TCIPs), operate at fractional occupancy of their protein targets, without genomic modifications to the cell or organism. The first TCIPs transiently re-localized elongation factors such as BRD4 (TCIP1, PMID 37495688) to loci regulated by the transcription factor BCL6, inducing the expression of pro-apoptotic genes regulated by BCL6. In new, unpublished work, CDK-TCIPs have been made to re-direct the activity of transcriptional elongation kinases such as CDK9, CDK12, or CDK13 to induce the expression of pro-apoptotic BCL6-target genes. Profiling in ∼900 barcoded cancer cell lines show that the molecules exhibit potent cell killing potency in a highly DLBCL lineage-restricted manner. Cytotoxicity to healthy lymphocytes is 100- to 10,000-fold lower, although germinal center B cells are ablated in a dose-dependent manner consistent with the role of BCL6 in the germinal center. Biochemical, cell biological, proteomic, and genomic studies demonstrate that CDK-TCIPs operate via a gain-of-function mechanism reliant on the ternary complex formed by the bivalent molecule. Instead of global enzyme inhibition or degradation, CDK-TCIPs borrow and re-localize a fraction of total CDK activity to BCL6-bound chromatin, producing pharmacology from the induction of pro-apoptotic gene transcription. The findings suggest a path to rational design of new gain-of-function chemotherapeutic strategies to rewire cell signaling using induced proximity. Citation Format: Sai Gourisankar, Roman Sarott, Basel Karim, Sabin Nettles, Haopeng Yang, Brendan Dwyer, Juste Simanauskaite, Jason Tse, Hind Abuzaid, Stephen M Hinshaw, Michael R Green, Gerald R Crabtree, Nathanael S Gray. Gain-of-function small molecules to reprogram oncogenic transcription in lymphoma [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-012.