High-Affinity Peptide-Drug Conjugate Ligands for the TRIM24 PHD and Bromodomain.

ABSTRACT: TRIM24 is an epigenetic transcriptional coregulator that "reads" KMe₃ and KAc histone modifications via its tandem plant homeodomain (PHD) and bromodomain (BRD), respectively. The PHD and BRD are potential therapeutic targets due to the roles of TRIM24 in breast cancer progression. However, there are currently no small-molecule ligands for the PHD, and existing TRIM24 BRD inhibitors lack selectivity over the main off-target, BRPF1. Here, we report the development of the first bivalent tool molecules capable of simultaneously engaging both the TRIM24 PHD and BRD. Key to this strategy was the identification of effective KMe₃ bioisosteres that enhance H3 peptide binding to the TRIM24 PHD. The most promising of these was incorporated into a nine amino acid H3-mimicking pe

SUBMITTER: Platt MA 

PROVIDER: S-EPMC12731528 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature