Design, synthesis, and pharmacological evaluation of novel isoindoline-based HPK1 degraders

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118366. doi: 10.1016/j.ejmech.2025.118366.
Zhisheng Zhang  1 ,  Xuan Zhang  1 ,  Tizhi Wu  1 ,  Shengnan Shi  1 ,  Jiahui Tu  2 ,  Manqi Zhang  1 ,  Yan Liang  3 ,  Mengyang Ma  1 ,  Sai Zhang  1 ,  Guangyue Gong  1 ,  Bing Huang  1 ,  Ahmed R Ali  4 ,  Zhixia Qiu  2 ,  Jinlei Bian  1 ,  Hongxi Wu  2 ,  Zhiyu Li  5 ,  Xi Xu  6 ,  Jubo Wang  7
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211100, PR China.
  • 2. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211100, PR China.
  • 3. Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, PR China.
  • 4. Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 5. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211100, PR China. Electronic address: [email protected].
  • 6. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211100, PR China. Electronic address: [email protected].
  • 7. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211100, PR China. Electronic address: [email protected].
PMID: 41273794 DOI: 10.1016/j.ejmech.2025.118366
Abstract

Hematopoietic progenitor kinase 1 (HPK1), a critical negative regulator of T-cell signaling, has emerged as an attractive yet challenging therapeutic target in immuno-oncology. Inspired by the clinical success of immunomodulatory drugs, we designed a series of novel proteolysis-targeting chimera (PROTAC) molecules targeting HPK1. Among these, compound D02 demonstrated potent HPK1 degradation (DC50 = 3.07 ± 1.81 nM, Dmax = 98.33 %) and effectively suppressed downstream phosphorylation of SLP-76 in Jurkat cells (IC50 = 11.38 nM). D02 potently induced IL-2 (EC50 = 4.51 nM) and IFN-γ (EC50 = 3.02 nM) secretion in human primary T cells. Notably, D02 exhibited favorable safety profiles in preliminary toxicological evaluations. We propose that D02 represents a promising candidate for further development of HPK1 degraders.

Keywords
CRBN; Degrader; HPK1; PROTAC.
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