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
  • 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.

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