the 22nd Pacific−Asian Marginal Seas meeting (PAMS)

This study addresses the unmet clinical need for targeting oncogenic transcription factors by discovering a first-in-class marine natural product that disrupts super-enhancer assembly. From the unexplored volcanic basin ecosystem of the South China Sea, we isolated the fungus Eupenicillium parva SCSIO 41302 associated with deep-sea sponges. Bioassay-guided isolation yielded the structurally unprecedented dimeric xanthone parvineol A, featuring a unique carbon skeleton with a complex polycyclic framework. Parvineol A exhibits exceptional potency against MYC-amplified hepatocellular carcinoma (IC50 = 8.3 nM) and demonstrates remarkable selectivity (>100-fold) over normal hepatocytes. Mechanistic investigation reveals that parvineol A specifically targets the intrinsically disordered region of the transcriptional coactivator BRD4, disrupting its phase-separated condensates at MYC super-enhancer loci without affecting bromodomain function. This disruption leads to selective dissociation of the Mediator complex and RNA polymerase II from MYC regulatory regions, resulting in rapid transcriptional silencing while sparing housekeeping genes. The target engagement was confirmed through cellular thermal shift assay, fluorescence recovery after photobleaching, and chromatin immunoprecipitation sequencing. Zebrafish xenograft models demonstrated significant tumor growth inhibition with favorable pharmacokinetic properties. This work presents a novel chemical scaffold that modulates transcriptional condensates and offers a promising therapeutic approach for MYC-driven malignancies.
 

Super-enhancer disassembly,Transcriptional condensates,Marine xanthone,MYC amplification,Phase separation,Intrinsically disordered regions,Deep-sea fungi,Targeted transcription therapy