Pharmacological targeting of IRF4 as a therapeutic strategy for multiple myeloma

Interferon regulatory factor 4 (IRF4) is an oncogenic transcription factor (TF) in several hematological malignancies. To date, no pharmacological agents have been developed specifically for IRF4 due to the challenging nature of targeting TFs. Here we first identified (S)-H1, a binder of IRF4, by targeting the SPI1-IRF4 interaction on IRF4's interferon association domain via high-throughput screening. Next, we successfully turned our binder into dIRF4-2, a first-in-class proteolysis-targeting chimera of IRF4, by linking (S)-H1 to E3 ligase ligands of cereblon. dIRF4-2 can induce highly selective proteasomal degradation of IRF4 and has strong cytotoxic effects in all multiple myeloma lines evaluated in vitro. Our study showcases methodology to effectively target the IRF family of TFs and illustrates how to convert an inert binder into a powerful chemical probe for studying the functions of important oncoproteins that are structurally difficult to target.