2. Academic Validation
  3. Design, synthesis, and pharmacological evaluation of novel isoindoline-based HPK1 degraders

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

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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