2. Academic Validation
  3. Discovery of a selective CDK7 PROTAC against acute leukemia with low platelet toxicity

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

  • Leukemia. 2026 May;40(5):925-933. doi: 10.1038/s41375-026-02925-2.
Yutong Tu # 1,  Xiaojia Cai # 2 3,  Zhaofan Tao 2 3,  Ruisen Zhang 4,  Xian Li 1,  Beijing Chen 1,  Hualin Zhang 2,  Xiaobei Hu 1,  Jiayi Ke 2 3,  Xiaoya Chen 2 3,  Xinyan Bai 1 3,  Jia Li 5 6 7,  Tianfeng Xu 8 9 10,  Yubo Zhou 11 12 13
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. [email protected].
  • 6 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. [email protected].
  • 7 State Key Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, PR China. [email protected].
  • 8 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 9 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 10 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 11 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. [email protected].
  • 12 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 13 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41882098 DOI: 10.1038/s41375-026-02925-2
Abstract

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.

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