2. Academic Validation
  3. Discovery of Novel, Potent, and Selective IRAK1 Inhibitors as Potential Therapeutics for Hepatocellular Carcinoma

Discovery of Novel, Potent, and Selective IRAK1 Inhibitors as Potential Therapeutics for Hepatocellular Carcinoma

  • J Med Chem. 2026 Feb 26;69(4):4270-4287. doi: 10.1021/acs.jmedchem.5c02988.
Wenjian Min 1 2 3,  Junfeng He 1 2 3,  Qiman Zhang 1 2 3,  Chunling Chen 1 2 3,  Yanyin Wang 1 2,  Yuanyuan Chen 1 2 3,  Yunchu Zhao 1 2 3,  Yi Hou 1 2 3,  Chengliang Sun 1 2 3,  Xiao Wang 1 2 3,  Kai Yuan 1 2 3,  Yasheng Zhu 1 2 3,  Peng Yang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Innovative Drug, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41637129 DOI: 10.1021/acs.jmedchem.5c02988
Abstract

Interleukin-1 receptor-associated kinase 1 (IRAK1) is a critical mediator of Toll-like Receptor (TLR)/interleukin-1 receptor (IL-1R) signaling, and its aberrant activation is implicated in the pathogenesis of various cancers, including hepatocellular carcinoma (HCC). However, the development of clinical IRAK1 inhibitors has been hampered by a lack of sufficient selectivity over Other kinases. Herein, we report the discovery of a novel IRAK1 Inhibitor, A34, identified through structure-based virtual screening and structural optimization. A34 potently inhibited IRAK1 with an IC50 value of 10.6 nM and demonstrated exceptional selectivity over 215 Other kinases, notably including IRAK4. Furthermore, A34 demonstrated significant anti-HCC activity both in vivo and in vitro, making it a valuable chemical probe for IRAK1 and a potential lead candidate for the treatment of HCC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-181712
    IRAK1抑制剂
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