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Nathanael Gray
Stanford University

Molecular Glues - from Protein Degradation to Transcription Factor Reprogramming

Description:
Molecular glues are small molecules that exert their pharmacological effects by inducing new protein-protein interactions. Originally identified as the mechanism of natural product macrocycles such as rapamycin and FK506, the discovery of new molecular glues has experienced a resurgence of interest. A key driver of this interest has been the development of both monovalent and bivalent molecular glues for E3 ligases that can induce ubiquitination and proteosome-mediated destruction of target proteins.  

Here we report the development of a new class of molecular glues targeting transcription factors which are DNA-binding proteins that regulate gene expression in mammalian cells. We focused on Bcl-6 which is a transcription factor that is critical to B-cell development but that becomes an oncogene in B-cell lymphomas such as Diffuse Large B-Cell Lymphoma  (DLBCL) and Chronic Lymphocytic Leukemia (CLL). We developed a series of bivalent small molecules that we call transcription factor induced chemical inducers of proximity (TCIPs) that induce neo-protein-protein interactions between Bcl6 and either the transcriptional co-activator protein Brd4 (TCIP1) or the RNA-pol2 kinase Cdk9 (TCIP2). We demonstrate that these molecules function as molecular glues that can convert Bcl6 from a transcriptional repressor to a potent activator of the apoptotic cell death program.  We demonstrate that the compounds rapidly modulate the Bcl6 gene expression program and induce apoptotic cell-death in Bcl6-dependent cellular models at picomolar concentrations. The lead compounds exhibit efficacy in PDX and germinal center B-cell murine models at well-tolerated doses. This works provides proof-of-concept that transcription factors can be reprogrammed by molecular glues which opens a host of therapeutic opportunities in oncology and many other diseases.