Enhancing Inhibition via Chemically Induced Proximity: A RIPTAC Targeting BCL6 & BET Proteins
- BCL6-directed BET inhibition: RIPTAC induces cooperative BCL6:BRD4 ternary complex formation, enhancing BET inhibition selectively in BCL6-high cancer cells
- Comparative mechanistic characterization of RIPTAC and TCIP: Structural and biophysical studies reveal that linker composition and BET warhead identity drive distinct ternary complex geometries and cooperativity profiles, providing a framework for understanding how bivalent molecule design shapes induced proximity pharmacology
- BCL6-mediated sequestration of BET proteins drives cytotoxicity: RNA-seq and BCL6-DNA binding mutant experiments show that cytotoxicity stems from enhanced BET inhibition, not transcriptional rewiring, suggesting the RIPTAC platform is broadly applicable to any disease context characterized by differential expression of a targetable protein