Discovery of Chemical and Biological Tools for Reprogramming the Transcription Factor BCL6 Through Chemically Induced Proximity Modalities

• Applicants: Professor Radoslaw Nowak, Ph.D.; Dr. Christian Steinebach
• Subject Area: Pharmacy ; Biochemistry ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552374678

Mutations in the oncogenic transcription factor B-cell lymphoma 6 (BCL6), which is a master regulator of B cell proliferation, often result in the formation of B cell lymphomas. Despite the notorious difficulty of targeting transcription factors with small molecules, BCL6 inhibitors, inducers of BCL6 polymerization, and degraders have been identified. However, these drugs typically demand significant concentrations to accomplish effects in living organisms. To surmount these constraints, more potent agents are required. Although new approaches to drug discovery, such as targeted protein degradation with Proteolysis Targeting Chimeras (PROTACs), hold great promise for improving drug efficacy, BCL6 remains a target for which neither degradation nor inhibition could completely halt tumor development. Recently, several proof-of-concept investigations have been undertaken to explore the potential of induced proximity modalities in Medicinal Chemistry and Chemical Biology. Transcriptional/epigenetic chemical inducers of proximity (TCIPs), which result in transcriptional activation by modulation of the protein-protein interactions (PPIs), are one of these novel platform techniques. This method was successfully applied to chemically activate the transcriptional repressor protein BCL6. A heterobifunctional molecule, TCIP1, was used to recruit BET family bromodomain BRD4, frequently found at super-enhancer regions, directly to BCL6, leading to transcription activation. Excitingly, activation of BCL6 resulted in more potent cell toxicity as compared to inhibitors or degraders of BCL6. This grant application aims to conduct further research on this intriguing new modality. We will investigate the precise mechanism of action of heterobifunctional and monovalent TCIPs, as such knowledge will facilitate the generalization of this example to other protein targets. We aim to identify novel effector proteins that can modify the interactome of BCL6 in a therapeutically significant manner. Furthermore, we will generate new chemical matter, consisting of both heterobifunctional and monovalent TCIPs, through solution- and solid-phase supported chemistry and multicomponent reactions. This cutting-edge project will develop experimental approaches for designing and using TCIP libraries that can modulate challenging drug targets such as BCL6 and further provide a blueprint for expanding to new target classes.

• DFG Programme: Research Grants
• International Connection: Austria, USA
• Cooperation Partners: Professor Dr. Eric Fischer; Professor Dr. Nathanael Gray; Georg Winter, Ph.D.
• Co-Investigator: Professor Dr. Felix Meissner