Discovery of a selective CDK7 PROTAC against acute leukemia with low platelet toxicity PMID: 41882098

ADC Targets in Oncology

2026-04-10

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

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.

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.