Abstract SY07-01: Gain-of-function small molecules to reprogram oncogenic transcription factors

Abstract A principle in the development of cancer therapies is that robust death of the malignant cell is critical. Highly effective strategies, such as immunotherapy, engage this principle. Here I will provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin’s lymphoma. We developed Transcriptional/epigenetic Chemical Inducers of Proximity (TCIPs): bivalent molecules that redirect epigenetic factors to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced complex of the histone acetyltransferases p300/CBP and BCL6 reveals how chance interactions between the proteins can be systematically exploited to produce exquisite potency and selectivity. Biophysical, proteomic, and genomic experiments demonstrate a sub-stoichiometric, gain-of-function mechanism. Our findings imply that the malignant function of an oncogenic driver can be systematically exploited using chemically induced proximity to activate robust cell death. Citation Format: Sai Gourisankar. Gain-of-function small molecules to reprogram oncogenic transcription factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY07-01.