机构：[1]Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi 530021, China.[2]Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.[3]Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Province Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou 314000, China.[4]Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.[5]Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.[6]Instrumental Analysis Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.[7]School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
Bruton's tyrosine kinase (BTK) is an attractive target in inflammatory and autoimmune diseases. However, the effectiveness of BTK inhibitors is limited by side effects and drug resistance. In this study, we report the development of novel BTK proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting outstanding degradation potency and efficiency in Mino cells (DC50, 4 h = 1.29 ± 0.3 nM, t1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteoclastogenesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs.
基金：
This work was supported by the National Natural Science
Foundation of China (No. 82173668 to C.J., 82003598 to L.Y.,
and 82260676 to P.X.), Jiangxi Provincial Natural Science
Foundation (20232BAB216131 to P.X.), and the Science and
Technology Projects of Ganzhou (202101094462 and
2023PNS26854 to P.X.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类|1 区医学
小类|1 区药物化学
最新[2025]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi 530021, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Huang Junli,Ma Zeli,Peng Xiaopeng,et al.Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases[J].Journal Of Medicinal Chemistry.2024,doi:10.1021/acs.jmedchem.3c01414.
APA：
Huang Junli,Ma Zeli,Peng Xiaopeng,Yang Zichao,Wu Yuhao...&Zeng Zhenhua.(2024).Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases.Journal Of Medicinal Chemistry,,
MLA：
Huang Junli,et al."Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases".Journal Of Medicinal Chemistry .(2024)
医学