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<p>BRPF1, a key component of the MOZ/MORF histone acetyltransferase complex, regulates chromatin remodeling and gene expression via its bromodomain, PHD fingers, and PWWP domain. Dysregulated BRPF1 is linked to neurodevelopmental disorders (e.g., syndromic mental retardation) and cancers (e.g., hepatocellular carcinoma, prostate cancer), making it a promising therapeutic target. This review summarizes BRPF1’s domain architecture, biological functions, and disease associations. It highlights progress in developing BRPF1 bromodomain inhibitors, including 1,3-dimethyl benzimidazolone derivatives (e.g., <i>GSK6853</i>), N-methylquinolin-2-one-based compounds (e.g., <i>NI-42</i>), and 3-acetylindole derivatives, along with dual-target inhibitors. Current limitations (suboptimal pharmacokinetics, poor selectivity, insufficient in vivo validation) are addressed. Finally, future directions (mechanistic exploration via advanced technologies, AI-aided drug design, and clinical translation) are proposed to advance BRPF1-targeted therapies.</p><p></p>

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Dual-target inhibitors based on brpf1: a review from medicinal chemistry perspectives

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Xuan Guan,
  • Dan Mei,
  • Xinyu Chen,
  • Xiaodiao Li,
  • Hongmei Yuan,
  • Dan Zhou

摘要

BRPF1, a key component of the MOZ/MORF histone acetyltransferase complex, regulates chromatin remodeling and gene expression via its bromodomain, PHD fingers, and PWWP domain. Dysregulated BRPF1 is linked to neurodevelopmental disorders (e.g., syndromic mental retardation) and cancers (e.g., hepatocellular carcinoma, prostate cancer), making it a promising therapeutic target. This review summarizes BRPF1’s domain architecture, biological functions, and disease associations. It highlights progress in developing BRPF1 bromodomain inhibitors, including 1,3-dimethyl benzimidazolone derivatives (e.g., GSK6853), N-methylquinolin-2-one-based compounds (e.g., NI-42), and 3-acetylindole derivatives, along with dual-target inhibitors. Current limitations (suboptimal pharmacokinetics, poor selectivity, insufficient in vivo validation) are addressed. Finally, future directions (mechanistic exploration via advanced technologies, AI-aided drug design, and clinical translation) are proposed to advance BRPF1-targeted therapies.