Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [ChIP-seq]. Homo sapiens

The addressable pocket of a target protein is often not functionally relevant. This is particularly true for multidomain gene regulatory proteins, such as the bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous human cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Overall design: TRIM24 localization to chromatin with treatments IACS-9571 and dTRIM24