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

作者：Chaoquan Tian, Hongguang Du, Wenjie Sha, L. Eduardo Wu, Zhixiao Yu, Haoming Song, Zihao Shen, Yan Dai, Shuhui Li, Wenyi Mei, Zhenjiang Zhao, Yanyan Diao, Hualiang Jiang, Honglin Li, Zhuo Chen · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00439 · 被引用次数：3 · 研究领域：Chronic Lymphocytic Leukemia Research、Toxin Mechanisms and Immunotoxins、PI3K/AKT/mTOR signaling in cancer

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(5 H )-one derivatives were designed and synthesized as noncovalent BTK inhibitors. Among them, representative compound 9 exhibited potent BTK inhibitory activity (IC 50 = 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.