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<p>Cyclin-dependent kinase 7 (CDK7), a key regulator of cell cycle progression and transcriptional control, has emerged as a promising therapeutic target in acute leukemia. While CDK7 inhibitors have shown antileukemic activity, their clinical utility is often restricted by dose-dependent thrombocytopenia. To overcome this challenge, we developed and characterized a series of CDK7-selective PROTAC degraders. By engaging the VHL E3 ligase, which is minimally expressed in platelets, CXJ2080 achieves tumor-selective CDK7 degradation with remarkable potency and selectivity (a DC<sub>50</sub> of 0.88 nM and &gt;98% degradation efficiency). This selective targeting spares platelets, thereby avoiding the hematologic toxicity associated with conventional CDK7 inhibitors. Mechanistically, CDK7 degradation disrupts the CDK7-cyclin H-MAT1 complex, simultaneously suppressing MYC-driven oncogenic signaling while activating the p53-p21 tumor suppressor axis. These effects have culminated in robust antileukemic activity in preclinical models, while preserving normal peripheral blood mononuclear cell (PBMC) function. Collectively, our findings establish CXJ2080 as a next-generation CDK7-targeted therapeutic agent with enhanced efficacy and reduced hematotoxicity, showing great promise for the treatment of acute leukemia.</p>

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Discovery of a selective CDK7 PROTAC against acute leukemia with low platelet toxicity

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Yutong Tu,
  • Xiaojia Cai,
  • Zhaofan Tao,
  • Ruisen Zhang,
  • Xian Li,
  • Beijing Chen,
  • Hualin Zhang,
  • Xiaobei Hu,
  • Jiayi Ke,
  • Xiaoya Chen,
  • Xinyan Bai,
  • Jia Li,
  • Tianfeng Xu,
  • Yubo Zhou

摘要

Cyclin-dependent kinase 7 (CDK7), a key regulator of cell cycle progression and transcriptional control, has emerged as a promising therapeutic target in acute leukemia. While CDK7 inhibitors have shown antileukemic activity, their clinical utility is often restricted by dose-dependent thrombocytopenia. To overcome this challenge, we developed and characterized a series of CDK7-selective PROTAC degraders. By engaging the VHL E3 ligase, which is minimally expressed in platelets, CXJ2080 achieves tumor-selective CDK7 degradation with remarkable potency and selectivity (a DC50 of 0.88 nM and >98% degradation efficiency). This selective targeting spares platelets, thereby avoiding the hematologic toxicity associated with conventional CDK7 inhibitors. Mechanistically, CDK7 degradation disrupts the CDK7-cyclin H-MAT1 complex, simultaneously suppressing MYC-driven oncogenic signaling while activating the p53-p21 tumor suppressor axis. These effects have culminated in robust antileukemic activity in preclinical models, while preserving normal peripheral blood mononuclear cell (PBMC) function. Collectively, our findings establish CXJ2080 as a next-generation CDK7-targeted therapeutic agent with enhanced efficacy and reduced hematotoxicity, showing great promise for the treatment of acute leukemia.