Covalent Degraders of Immune Regulatory Transcription Factors IRF8 and IRF5.

ABSTRACT: Transcription factors are among the most challenging targets for drug discovery due to their lack of classical binding pockets and high degree of intrinsic disorder, despite the therapeutic importance of many of these proteins. IRF5 and IRF8 are key transcriptional regulators of innate immune signaling that orchestrate pro-inflammatory gene expression programs in response to stimuli such as toll-like receptor activation, making them central players in autoimmune and inflammatory diseases. Despite their therapeutic interest, direct targeting of IRF5 and IRF8 has remained challenging. Here, we screened a library of cysteine-reactive covalent ligands to identify hits that could degrade IRF5. We identified acrylamide EN1033 as the top hit, which not only led to IRF5 loss in a proteasome-depend

SUBMITTER: Do TC 

PROVIDER: S-EPMC12324457 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature