2. Academic Validation
  3. Discovery of a New and Selective HPK1 PROTAC for Enhancing Tumor Immunotherapy through Eliminating GLK Degradation

Discovery of a New and Selective HPK1 PROTAC for Enhancing Tumor Immunotherapy through Eliminating GLK Degradation

  • J Med Chem. 2025 Jun 12;68(11):10800-10822. doi: 10.1021/acs.jmedchem.4c02972.
Mingfei Wu 1,  Xinfei Mao 1,  Yiquan Wu 1,  Wentao Wang 1,  Yuyuan Jin 2,  Hengyuan Yu 1,  Liuzhi Hu 1,  Zheyuan Shen 1,  Liteng Shen 1,  Shenxin Zeng 2,  Tengfei Xu 1,  Yong Chen 1,  Bo Zhang 3,  Nengming Lin 3,  Jinxin Che 1 4,  Wenhai Huang 2,  Xiaowu Dong 1
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Center of Safety Evaluation and Research, School of Pharmacy, Hangzhou Medical College, Hangzhou 310013, China.
  • 3 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310024, China.
  • 4 Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou 310058, Zhejiang, China.
PMID: 40375722 DOI: 10.1021/acs.jmedchem.4c02972
Abstract

HPK1 is an attractive therapeutic target for tumor immunotherapy. Nevertheless, the formidable challenge selectivity over GLK and limited antitumor efficacy of HPK1 inhibitors and PROTACs impeded their developments. Here, we demonstrated that blocking GLK alone or simultaneous blocking both GLK and HPK1 could reduce immune activation through siRNA, which underscores the necessity for designing selective HPK1 degraders. Given the differences in spatial tolerance between HPK1 and GLK, we successfully obtained a degrader, designated E3, which exhibits a DC50 of 3.16 nM for HPK1 and demonstrates at least a 1000-fold selectivity over GLK. Notably, E3 displayed a superior capacity for promoting immune activation. Oral administration of E3 combined with PDL-1 antibody showed significant antitumor activity. In conclusion, the availability of E3 provides a structural foundation for the development of selective HPK1 PROTACs.

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