A novel small-molecule inhibitor of IRF4 selectively suppresses multiple myeloma

Multiple myeloma (MM) is a highly aggressive hematologic malignancy that exploits transcriptional networks driven by IRF4 (interferon regulatory factor 4), an oncogenic protein that has been shown to directly mediate MM transcriptional networks. IRF4 overexpression promotes the proliferation of MM and the regeneration of progenitor or treatment-resistant cells. However, no known small molecules directly bind to IRF4, and the lack of potent, selective IRF4 inhibitors requires further clinical investigation. Through screening and functional validation, we identified G1126, a bisnoralcohol derivative, as a novel small molecule inhibitor of IRF4 that selectively targets IRF4 to block MM proliferation in vitro , which exhibited high activity with a half inhibitory concentration (IC 50 ) value of approximately 100 nM in H929 and MM.1R cells and impeded tumor progression in a xenograft model while sparing normal hematopoietic stem cells To further reveal the molecular mechanism by which IRF4 inhibition mediates MM oncogenesis linked to the downregulation of genes, including E2F5, SLAMF7, c-Myc, CDK6, ELL2 and PRDM1. Meanwhile, G1126 reduced lenalidomide-resistant MM cells and increased responsiveness to chemotherapy in MM. These findings elucidate opportunities for IRF4-based MM therapeutic development and promote IRF4 small molecule inhibitors to impair disease progression in MM.