Induced Proximity Therapeutics to Rewire Oncogenic Transcription

Host: Professor Alessio Ciulli 

Venue: MSI Small Lecture Theatre, SLS

This seminar is fully funded by external sources

Abstract

A principle in the development of cancer therapies is that robust death of the malignant cell is critical. However, traditional cancer therapies often rely on inhibiting essential proteins, risking toxicity in healthy cells. I will present an alternative approach that leverages chemically induced proximity to rewire oncogenes to selectively activate apoptosis, using Transcriptional/Epigenetic Chemical Inducers of Proximity (TCIPs)1-3. These small molecules redirect chromatin regulators –including elongation factors, transcriptional kinases, and acetyltransferases – to activate cell death genes silenced by cancer drivers such as BCL6 in diffuse large B cell lymphomas. Structural and mechanistic studies reveal a sub-stoichiometric, gain-of-function mechanism that decouples efficacy from on-target toxicity. Induced proximity thus enables systematic exploitation of the malignant function of an oncogenic driver to achieve context-specific transcriptional control, offering a new direction for targeted cancer therapeutics.