SRE109

SRE109 is a potent small molecule splicing modulator that selectively targets the Signal Transducer and Activator of Transcription 1 (STAT1) gene. Discovered using the AI-driven VoyageR Engine platform, SRE109 promotes the retention of a highly conserved "poison exon" (PE) within the STAT1 transcript. This alternative splicing event introduces a premature in-frame stop codon, which triggers the nonsense-mediated decay (NMD) pathway, leading to the degradation of STAT1 mRNA and a subsequent reduction in STAT1 protein levels. SRE109 exhibits an IC50 of 30nM and has demonstrated the ability to block interferon-gamma (IFN-γ) induced transcriptomic and cytokine responses in preclinical models of myeloproliferative neoplasms (MPN), acute myelogenous leukemia (AML), and benign erythropoiesis. It represents a novel therapeutic strategy for downregulating STAT1-driven pathological processes and is more potent and selective than the tool compound branplam.