Dear Editor,Proteolysis-targeting chimera (PROTAC) is a newly emerging strategy that harnesses the ubiquitin–proteasome system (UPS) to knock down target proteins for novel therapies1. 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 malignancies2.

亲爱的编辑，针对嵌合体的蛋白水解（PROTAC）是一种新兴的策略，它利用泛素-蛋白酶体系统（UPS）敲除靶蛋白进行新疗法1。这种方法迅速引起了学术界和工业界的关注。我们设计了第一个PROTAC降解剂，以靶向布鲁顿酪氨酸激酶（BTK），这是B细胞存活和功能的关键蛋白，目的是治疗突变的BTK C481S诱导的依鲁替尼耐药B细胞恶性肿瘤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 BTK3. 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 effects3.

然后，我们通过强化配体和接头优化开发了新一代BTK降解剂L18I，在降解BTK3方面表现出改善的溶解度和优异的效率。L18I在人B细胞衍生的非霍奇金淋巴瘤中对不同突变形式的BTK蛋白表现出优异的降解性，并且还抑制异种移植小鼠中活化的人B细胞样弥漫性大B细胞淋巴瘤肿瘤细胞的生长而没有明显的副作用3。

Apart from these BTK-mediated B-cell tumor studies4, numerous evidence has highlighted the significant involvement of BTK dysfunction in autoimmune diseases5. 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 concerns5.

除了这些BTK介导的B细胞肿瘤研究4外，许多证据都强调了BTK功能障碍在自身免疫性疾病中的重要作用5。事实上，最近已经研究了BTK抑制剂用于治疗自身免疫性疾病，然而，由于临床疗效和安全性问题，临床试验既有成功也有失败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 literature2,3, the application of BTK-targeting PROTACs in autoimmune diseases is lack. We studied the effects of the BTK degrader L18I on autoimmune diseases by using BM12 splenocytes-induced lupus disease model and the pristane-induced diffuse alveolar hemorrhage (DAH) disease model.Firstly, the degradation of BTK by L18I.

尽管如本报告（补充图S1a–c）和我们的文献2,3所示，用于BTK降解的PROTAC显示出最小的脱靶效应，但缺乏针对BTK的PROTAC在自身免疫性疾病中的应用。我们通过使用BM12脾细胞诱导的狼疮疾病模型和姥鲛烷诱导的弥漫性肺泡出血（DAH）疾病模型研究了BTK降解物L18I对自身免疫性疾病的影响。首先，L18I对BTK的降解。

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Download referencesAcknowledgementsThis study has been supported by funds from Tsinghua University Spring Breeze Fund, Center for Life Sciences, Institute for Immunology at Tsinghua University, and Vanke School of Public Health at Tsinghua University, and grants from Ministry of Science and Technology of China Grants (2021YFC2300500, 2021YFC2302403, 2020YFE0202200, 2021YFA1300200 and 2021YFA1302100), the National Natural Science Foundation of China (32141004, 81825010, 81730043, 81621002, 82125034, 82330115 and 81970179), Beijing Natural Science Foundation (Z220023), Science Foundation of Peking University Cancer Hospital (JC202401).Author informationAuthor notesThese authors contributed equally: Can Zhu, Zimo Yang, Yuxiao Zhang, Zhenjun Li, Guangchen Li.Authors and AffiliationsState Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing Tsinghua Changgeng Hospital, Tsinghua University, Beijing, ChinaCan Zhu, Yuxiao Zhang, Bing Yang, Na Kang & Wanli LiuThe First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, Anhui, ChinaCan ZhuMOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, ChinaZimo Yang, Guangchen Li, Yonghui Sun & Yu RaoKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, ChinaZhenjun Li, Jingwen Wang & Ning DingAuthorsCan.

下载参考文献致谢本研究得到了清华大学春风基金、生命科学中心、清华大学免疫学研究所和清华大学万科公共卫生学院的资助，以及中国科学技术部拨款（2021YFC2300500201YFC2302402020YFE02022002021YFA1300200和2021YFA1302100）、国家自然科学基金（32141004、81825010、81730043、81621002、82125034、82330115和81970179）、北京自然科学基金（Z220023）、北京大学癌症科学基金的资助医院（JC202401）。作者信息作者注意到，这些作者做出了同样的贡献：朱灿，杨子默，张玉晓，李振军，李光臣。作者和附属机构清华大学生命科学学院膜生物学国家重点实验室，清华大学北京生命科学中心，免疫学研究所，教育部蛋白质科学重点实验室，北京清华大学长庚医院慢性病免疫学研究重点实验室，北京，中国朱灿，张玉晓，杨冰，刘南康和刘万丽安徽医科大学第一附属医院和安徽医科大学临床免疫学研究所，安徽合肥，中国教育部重点实验室药物科学学院蛋白质科学重点实验室清华大学生物有机磷化学与化学生物学系，北京，中国杨子默，李光臣，孙永辉，余若基致癌作用与转化研究实验室（教育部），。

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PubMed Google ScholarContributionsAll the authors have contributed to this manuscript. C.Z. drafted the manuscript. C.Z., Z.Y., Y.Z., Z.L., G.L., B.Y., and J.W. performed the experiments and statistical analysis. N.K., Y.S., and N.D. revised the manuscript. W.L., Y.R., and N.D.

PubMed谷歌学术贡献所有作者都为这份手稿做出了贡献。C、 Z.起草了手稿。C、 Z.，Z.Y.，Y.Z.，Z.L.，G.L.，B.Y。和J.W.进行了实验和统计分析。N、 K.，Y.S。和N.D.修改了手稿。W、 L.，Y.R。和N.D。

designed, revised and approved the final manuscript.Corresponding authorsCorrespondence to.

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Ning Ding, Yu Rao or Wanli Liu.Ethics declarations

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作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleZhu, C., Yang, Z., Zhang, Y. et al. PROTAC for Bruton’s tyrosine kinase degradation alleviates inflammation in autoimmune diseases.

转载和许可本文引用本文Zhu，C.，Yang，Z.，Zhang，Y。等人。用于布鲁顿酪氨酸激酶降解的PROTAC可减轻自身免疫性疾病的炎症。

Cell Discov 10, 82 (2024). https://doi.org/10.1038/s41421-024-00711-xDownload citationReceived: 26 September 2023Accepted: 13 July 2024Published: 06 August 2024DOI: https://doi.org/10.1038/s41421-024-00711-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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