State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113040. doi: 10.1016/j.intimp.2024.113040. Epub 2024 Aug 31.
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder involving multiple organs and systems. There is growing evidence that autoreactive B cells occupy a central role in the occurrence and progression of SLE due to their ability to generate pathogenic autoantibodies. Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), a crucial intracellular kinase regulating B cell development and function, emerge as a new strategy to treat SLE in recent years and are superior to biologic agents depleting B cells in many aspects. Supportive data obtained from lupus-prone mice preliminarily demonstrated the promising therapeutic potential of BTK inhibition. However, these BTK inhibitors, including elsubrutinib, evobrutinib, etc., mostly face with unsatisfactory efficacy and certain safety issues during clinical use, driving the quest for new-generation inhibitors with improved potency and higher selectivity. This paper elaborates the importance of BTK involvement in SLE pathogenesis, reviews the clinical research progress of BTK inhibitors for SLE and discusses limitations and challenges the drugs met in development, in order to contribute to a deeper understanding of disease mechanism and provide a reference for new-generation BTK inhibitor research.
系统性红斑狼疮（SLE）是一种累及多器官、多系统的慢性自身免疫性疾病。越来越多的证据表明，由于自身反应性 B 细胞能够产生致病性自身抗体，因此在 SLE 的发生和进展中占据核心地位。近年来，针对布鲁顿酪氨酸激酶（BTK）的小分子抑制剂作为一种治疗 SLE 的新策略出现，该激酶是调节 B 细胞发育和功能的关键细胞内激酶，在许多方面优于耗竭 B 细胞的生物制剂。来自狼疮易感小鼠的支持性数据初步表明 BTK 抑制具有有前景的治疗潜力。然而，这些 BTK 抑制剂，包括伊布替尼、奥布替尼等，在临床应用中大多面临疗效不理想和某些安全性问题，这促使人们寻求具有更高效力和更高选择性的新一代抑制剂。本文阐述了 BTK 在 SLE 发病机制中的重要性，综述了 BTK 抑制剂治疗 SLE 的临床研究进展，并讨论了药物在开发过程中遇到的局限性和挑战，以期加深对疾病机制的理解，并为新一代 BTK 抑制剂的研究提供参考。
