2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2- a]quinoxalin-4(5 H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors

Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2- a]quinoxalin-4(5 H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors

  • J Med Chem. 2025 Apr 24;68(8):8841-8860. doi: 10.1021/acs.jmedchem.5c00439.
Chaoquan Tian 1,  Husheng Du 1,  Wenjie Sha 1,  Lingkang Wu 1,  Zhixiao Yu 1,  Haoming Song 1,  Zihao Shen 1,  Yan Dai 1,  Shuhui Li 1,  Wenyi Mei 1,  Zhenjiang Zhao 1,  Yanyan Diao 2,  Hualiang Jiang 1 3,  Honglin Li 1 2,  Zhuo Chen 1
Affiliations

Affiliations

  • 1 School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
PMID: 40191988 DOI: 10.1021/acs.jmedchem.5c00439
Abstract

Bruton's tyrosine kinase (Btk) is a therapeutic target for B-cell-driven malignancies. Most of the approved covalent Btk inhibitors are associated with treatment limitations due to off-target toxicity and drug resistance. Developing noncovalent Btk inhibitors is a promising strategy to address unmet clinical needs. Here, a novel series of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives were designed and synthesized as noncovalent Btk inhibitors. Among them, representative compound 9 exhibited potent Btk inhibitory activity (IC50 = 21.6 nM) and excellent selectivity against a panel of 468 kinases. Moreover, the oral exposure property of compound 9 was improved, and the antitumor efficacy of compound 9 (TGI = 64.4%) was superior to the lead S2 (TGI = 28.7%) and Ibrutinib (TGI = 41.1%) in the U-937 xenograft models at an oral dosage of 50 mg/kg. All these results suggest that compound 9 is a potent, selective, and orally available noncovalent Btk Inhibitor worthy of further development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172589
    BTK抑制剂
    Btk
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