YK-4-279

YK-4-279 is a first-in-class small molecule inhibitor designed to disrupt the protein-protein interaction between the EWS-FLI1 oncoprotein and RNA helicase A (RHA/DHX9). This interaction is critical for the transcriptional activity of EWS-FLI1, which drives the pathogenesis of Ewing sarcoma. Beyond Ewing sarcoma, YK-4-279 has shown activity in other cancers driven by ETS family transcription factor fusions, such as ERG- or ETV1-positive prostate cancer. By binding to RHA and preventing its recruitment to ETS-fusion proteins, the compound inhibits tumor cell growth, invasion, and metastasis. It was discovered at Georgetown University and served as the lead compound for the clinical-stage derivative TK216.