Discovery of Imidazo[1,2-<i>b</i>]pyridazine Derivatives as Potent and Highly Selective Irreversible Bruton’s Tyrosine Kinase (BTK) Inhibitors
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 <b>22</b>, an imidazo[1,2-<i>b</i>]pyridazine derivative, exhibiting potent BTK inhibition (IC<sub>50</sub> 1.3 nM) with excellent selectivity across 310 kinases. Compound <b>22</b> 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 <b>22</b>, named TM471-1, into Phase I clinical trials (CXHL2300956).
Authors
- Haoyi Zhang
- Hui Jun Ren (ORCID: https://orcid.org/0000-0003-1698-5505)
- Wei Wang (ORCID: https://orcid.org/0000-0002-9616-1145)
- Huayan Yang (ORCID: https://orcid.org/0000-0003-2981-6727)
- Yi Xiong (ORCID: https://orcid.org/0000-0003-3086-0282)
- Chunhua Ma (ORCID: https://orcid.org/0000-0001-7613-6471)
- Wei Li (ORCID: https://orcid.org/0000-0003-4205-9054)
- Yue Wang (ORCID: https://orcid.org/0000-0002-8020-3937)
- Dandan Zhang (ORCID: https://orcid.org/0000-0001-5305-9856)
- Di Wang (ORCID: https://orcid.org/0000-0002-3940-6177)
- Chenchen Zhang (ORCID: https://orcid.org/0000-0001-8563-5002)
- Zhimin Li (ORCID: https://orcid.org/0000-0003-0972-952X)
- Jing Gao (ORCID: https://orcid.org/0000-0001-5099-6991)
- Yuqin Jiang (ORCID: https://orcid.org/0009-0000-9607-0051)
- Biao Li (ORCID: https://orcid.org/0000-0001-7670-0888)
- Yu Du (ORCID: https://orcid.org/0000-0002-9654-164X)
- Qingjie Ding (ORCID: https://orcid.org/0000-0003-1099-3125)
- Jie Zhao (ORCID: https://orcid.org/0000-0003-4797-8957)
- Dongfang Liu (ORCID: https://orcid.org/0000-0002-1203-9186)
- Guiqing Xu
- Xing He (ORCID: https://orcid.org/0000-0003-3003-9830)
- Jiajun Geng
Institutions
- Institute for Biomedicine (IT)
- Ministry of Education (BD)
- Artificial Intelligence in Medicine (Canada) (CA)
- Henan Normal University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03083
- Citations
- 3
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 4.88
Funders
- Henan Normal University
- National Natural Science Foundation of China
- Education Department of Henan Province
- Henan Provincial Science and Technology Research Project
- Science and Technology Innovation Talents in Universities of Henan Province