BRD4 bromodomain targeting for new therapeutic frontiers

Bromodomain-containing protein 4 (BRD4), a critical transcriptional coactivator, drives cancers and inflammation through bromodomain-dependent and non-canonical mechanisms, with resistance to bromodomain inhibitors necessitating alternative therapeutic strategies.

Emerging non-canonical functions, including extra-terminal (ET) domainmediated scaffolding of oncogenic complexes, kinase/histone acetyltransferase (HAT) enzymatic activities, isoformspecific condensate dynamics, and post-translational modification (PTM)- mediated adaptive rewiring, underlie transcriptional resilience in tumors and immune dysregulation.

Multidimensional targeting platforms, including BRD4 degraders [proteolysistargeting chimeras (PROTACs)/chemical inducers of degradation (CIDEs)], chemical inducers of proximity [transcriptional/ epigenetic chemical inducers of proximity (TCIPs)/regulated induced proximitytargeting chimeras (RIPTACs)], ET domain peptide inhibitors, PTM modulators (e.g., phosphatase-targeting chimeras; PhosTACs), and condensate disruptors, overcome compensatory resistance and redefine precision intervention in oncology and inflammation.

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(25)00224-X

https://sciencemission.com/BRD4-bromodomains