EN1033 is a covalent immune regulatory transcription factor 5/8 (IRF5/8) molecular glue degrader. EN1033 degrades IRF5 in a proteasome-dependent manner. EN1033 engages and degrades IRF8 more robustly and rapidly. EN1033 covalently targets C28 and C223 to destabilize and degrade IRF5 and IRF8 respectively, thereby inhibiting their pro-inflammatory transcriptional activity. EN1033 serves as a promising tool for the study of autoimmune and inflammatory disorders.
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