Discovery of Imidazo[1,2- b]pyridazine Derivatives as Potent and Highly Selective Irreversible Bruton's Tyrosine Kinase (BTK) Inhibitors

  • J Med Chem. 2025 Jun 12;68(11):10897-10929. doi: 10.1021/acs.jmedchem.4c03083.
Dandan Zhang  1 ,  Jie Zhao  1 ,  Guiqing Xu  1 ,  Yue Wang  1 ,  Yang Li  1 ,  Hanxiao Ren  1 ,  Jiajun Geng  1 ,  Yu Du  1 ,  Chenchen Zhang  1 ,  Shouning Yang  1 ,  Dongfang Liu  2 ,  Jiajing Gao  2 ,  Yi Xiong  2 ,  Haoyi Zhang  2 ,  Wei Li  1 ,  Wei Wang  3 ,  Di Wang  3 ,  Biao Li  3 ,  Xing He  1 ,  Chunhua Ma  1 ,  Yuqin Jiang  1 ,  Qingjie Ding  1
Affiliations
  • 1. Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
  • 2. Henan Zhiwei Biomedicine Co., Ltd., Xinxiang, Henan 453007, China.
  • 3. Key Laboratory of Artificial Intelligence and Personalized Learning in Education of Henan Province, College of Computer and Information Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
PMID: 40369903 DOI: 10.1021/acs.jmedchem.4c03083
Abstract

Bruton's tyrosine kinase (Btk) is a crucial enzyme in the B cell receptor signaling pathway. It plays a central role in B cell development, maturation, and signaling. This role extends to the survival, proliferation, and migration of malignant B cells, making Btk an intriguing target in the search for therapeutics against B cell malignancies. Our research focused on the discovery of a covalent inhibitor of Btk with good selectivity and potency and a favorable safety profile. We identified compound 22, an imidazo[1,2-b]pyridazine derivative, exhibiting potent Btk inhibition (IC50 1.3 nM) with excellent selectivity across 310 kinases. Compound 22 demonstrated favorable pharmacokinetics and a robust safety profile. In a xenograft model, it significantly inhibited tumor growth, achieving complete tumor regression in 7 out of 10 mice at a dose of 15 mg/kg. This promising preclinical data led to the advancement of compound 22, named TM471-1, into Phase I clinical trials (CXHL2300956).

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