摘要：SummaryThe BET-bromodomain protein BRD4 uses two bromodomains to target acetyl-histones and other domains to recruit P-TEFb and other transcription factors to stimulate transcription of proto-oncogenes and key cell identity genes. Recent studies show that its ability to form phase-separated condensates that cluster preferentially at the super-enhancer regions of target genes is key for BRD4 to exert its functions. Here, we describe the identification of a natural product called PCG frompolygonum cuspidatumSieb.et Zucc., a traditional Chinese medicinal herb, that directly binds to BRD4. This binding inhibits BRD4 phase separation, turns dynamic BRD4 nuclear condensates into static aggregates, and effectively shuts down transcription of BRD4-dependent genes. Thus, through PCG we have discovered a BET inhibitor that not only selectively targets BRD4 but also works by suppressing phase separation, a mechanism of action that is different from those of the other known BET inhibitors.Graphical abstractDisplay OmittedHighlights•Natural product PCG induces aggregation of BRD4 but no other BET family proteins•PCG targets proline-rich sequences in BRD4 intrinsically disordered region•PCG turns phase-separated BRD4 into static aggregatesin vivoandin vitro•The PCG-induced aggregation inhibits BRD4-dependent transcriptionBiological sciences; Molecular biology; Natural product biochemistry
