Chemical inducers of proximity (CIPs) are small molecules that induce proximity between two proteins, promoting protein–protein interactions and thereby regulating cellular processes. This strategy of artificially bringing two proteins together to elicit a specific biological effect has been widely applied, with well-known examples including PROTACs and molecular glues. Beyond applications involving the ubiquitin–proteasome system and transcription factors, this approach can also be used to induce interactions involving membrane proteins and lysosomal membrane proteins, making it an important strategy in drug design.
In 2023, Gray’s and Crabtree’s groups at Stanford reported a new class of molecules known as transcriptional/epigenetic chemical inducers of proximity (TCIPs). These molecules can recruit endogenous cancer-driving proteins or their downstream transcription factors to the promoters of cell-death genes, thereby activating their expression. (Nature 2023, 620, 417–425.)
1) BCL6 as a cancer driver in DLBCL
In diffuse large B-cell lymphoma (DLBCL), the transcription factor BCL6 is aberrantly activated. BCL6 can bind to the promoters of pro-apoptotic genes and repress their expression, thereby blocking tumor-cell apoptosis and driving abnormal cancer-cell proliferation and disease progression.
2) TCIP1 rewires transcriptional regulation to activate apoptosis
The research team designed a small molecule, TCIP1, that induces proximity between BCL6 and BRD4, rewiring the transcriptional regulatory program at target pro-apoptotic genes. This interaction initiates transcriptional elongation and relieves the repression of apoptosis, while causing only a modest reduction in BRD4 binding at enhancer regions (approximately 10%).
Through this gain-of-function mechanism, TCIP1 enables precise targeted regulation. In addition, TCIP1 demonstrates excellent cellular and tissue selectivity in killing chemotherapy-resistant, TP53-mutant DLBCL cells.
3) A new strategy for targeted gene regulation
The TCIP concept represents a departure from traditional anticancer drug-design strategies. In addition to its potential application in targeted lymphoma therapy, this approach may be extended to regenerative medicine, developmental disorders, and other diseases involving dysregulated gene expression, providing a new strategy for the development of next-generation anticancer therapeutics.
Production of TCIPs (Nature 2023, 620, 417-425.)