PROTAC for Bruton’s tyrosine kinase degradation alleviates inflammation in autoimmune diseases

作者：Can Zhu, Zimo Yang, Yu‐Xiao Zhang, Zhenjun Li, Guangchen Li, Bing Yang, Na Young Kang, Jingwen Wang, Yonghui Sun, Ning Ding, Yu Rao, Wanli Liu · 发表于：Cell Discovery · 年份：2024 · DOI：10.1038/s41421-024-00711-x · 被引用次数：22 · 研究领域：Chronic Lymphocytic Leukemia Research、Protein Degradation and Inhibitors、Lymphoma Diagnosis and Treatment

Proteolysis-targeting chimera (PROTAC) is a newly emerging strategy that harnesses the ubiquitin–proteasome system (UPS) to knock down target proteins for novel therapies 1 . This approach has rapidly garnered attention in both academia and industry fields. We designed the first PROTAC degrader to target Bruton’s tyrosine kinase (BTK), a key protein for B-cell survival and function, for the purpose of treating mutated BTK C481S- induced Ibrutinib-resistant B-cell malignancies 2 . We then developed a new generation of BTK degrader L18I through intensive ligand and linker optimizations, exhibiting improved solubility and superior efficiency in degrading BTK 3 . L18I exhibits excellent degradability towards different mutated forms of BTK proteins in human B-cell-derived non-Hodgkin lymphoma, and also inhibits the growth of activated human B-cell-like diffuse large B-cell lymphoma tumor cell in xenograft mice without obvious side effects 3 . Apart from these BTK-mediated B-cell tumor studies 4 , numerous evidence has highlighted the significant involvement of BTK dysfunction in autoimmune diseases 5 . Indeed, BTK inhibitors have been recently investigated for the treatment of autoimmune diseases, however, there are both successes and failures in clinical trials due to clinical efficacy and safety concerns 5 . Although PROTACs for BTK degradation have been shown minimal off-target effects as demonstrated in this report (Supplementary Fig. S1a–c ), and in our literature 2 , 3 , the...