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<p>The abnormal function of histone lysine demethylase 6B (KDM6B) is closely associated with the development and progression of various human diseases, including cancer, inflammatory disorders, and psychiatric conditions, supporting KDM6B as a significant therapeutic target. However, the development of potent and selective KDM6B inhibitors remains a critical unmet need. Based on the hit compound (<b>A01</b>) discovered by enzyme-level screening, a series of derivatives with quinazoline scaffold were designed, synthesized and identified as KDM6B inhibitors. Among these, compound <b>13k</b> exhibited optimal potency (IC<sub>50</sub> = 1.8&#xa0;μM) with superior selectivity over other JMJD subfamily members. Furthermore, <b>13k</b> upregulates histone methylation levels in THP-1 cells, highlighting its functional effect in a cellular context. This study provides a promising scaffold for developing selective KDM6B inhibitors, as well as delivers a tool compound for probing the biological functions of KDM6B. These findings offer a potential lead for future KDM6B-targeted drug discovery.</p> Graphical abstract <p></p>

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Design and synthesis of novel quinazoline derivatives as KDM6B selective inhibitors

  • 期刊论文

  • 发表日期：

    2025年12月19日

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  • Dongxuan Ni,
  • Hongyuan Zhou,
  • Qijing Fan,
  • Jijian Yang,
  • Ruoxi Xue,
  • Xingjie Zhang,
  • Bin Liang,
  • Ruihan Zhang,
  • Weilie Xiao

摘要

The abnormal function of histone lysine demethylase 6B (KDM6B) is closely associated with the development and progression of various human diseases, including cancer, inflammatory disorders, and psychiatric conditions, supporting KDM6B as a significant therapeutic target. However, the development of potent and selective KDM6B inhibitors remains a critical unmet need. Based on the hit compound (A01) discovered by enzyme-level screening, a series of derivatives with quinazoline scaffold were designed, synthesized and identified as KDM6B inhibitors. Among these, compound 13k exhibited optimal potency (IC50 = 1.8 μM) with superior selectivity over other JMJD subfamily members. Furthermore, 13k upregulates histone methylation levels in THP-1 cells, highlighting its functional effect in a cellular context. This study provides a promising scaffold for developing selective KDM6B inhibitors, as well as delivers a tool compound for probing the biological functions of KDM6B. These findings offer a potential lead for future KDM6B-targeted drug discovery.

Graphical abstract