Saba Afsheen, Liu Rui-Chen, Wang Si-Xi, Shehzadi Kiran, Xu Wei-Hai, Xu Yan, Liang Jian-Hua, Yu Ming-Jia
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China.
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
ACS Omega. 2025 Jul 22;10(30):33481-33496. doi: 10.1021/acsomega.5c03682. eCollection 2025 Aug 5.
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by progressive neurological impairment. Bruton's tyrosine kinase (BTK) has emerged as a crucial therapeutic target due to its role in B-cell activation and innate immune signaling. While BTK inhibitors (BTKi) have shown promise for treating MS and inflammatory disorders, their high toxicity and off-target kinase inhibition pose challenges, particularly given that many patients experience mild symptoms. This study presents , a structurally optimized, highly selective BTKi designed to minimize drug-induced liver injury (DILI) and improve blood-brain barrier (BBB) permeability. Using scaffold hopping, the nitro-substituted aromatic scaffold was replaced with a trifluoromethyl-substituted heterocycle, significantly reducing hepatotoxicity while enhancing binding interactions with key BTK residues (CYS481, GLY480, and ASP539). also demonstrates lower CYP inhibition, reduced AMES toxicity, and improved membrane absorption, ensuring better druggability. Computational analyses, including site-directed mutation studies, molecular dynamics (MD) simulations, and quantum chemical analysis, confirmed 's high binding specificity, reduced off-target effects, and strong conformational stability across BTK variants. mitigates off-target effects through structural optimization of the BTK binding pocket, particularly at CYS481, enhancing binding specificity and reducing nonspecific interactions across BTK mutants. These findings establish as a next-generation BTKi with enhanced safety and therapeutic potential for autoimmune and inflammatory diseases, particularly MS.
多发性硬化症（MS）是一种慢性自身免疫性脱髓鞘疾病，其特征为进行性神经功能损害。布鲁顿酪氨酸激酶（BTK）因其在B细胞活化和固有免疫信号传导中的作用，已成为一个关键的治疗靶点。虽然BTK抑制剂（BTKi）已显示出治疗MS和炎症性疾病的潜力，但其高毒性和脱靶激酶抑制带来了挑战，特别是考虑到许多患者症状较轻。本研究展示了一种结构优化、高度选择性的BTKi，旨在将药物性肝损伤（DILI）降至最低，并提高血脑屏障（BBB）通透性。通过骨架跃迁，硝基取代的芳香族骨架被三氟甲基取代的杂环所取代，显著降低了肝毒性，同时增强了与关键BTK残基（CYS481、GLY480和ASP539）的结合相互作用。该BTKi还表现出较低的细胞色素P450抑制作用、降低的AMES毒性和改善的膜吸收，确保了更好的成药性。包括定点突变研究、分子动力学（MD）模拟和量子化学分析在内的计算分析证实了该BTKi具有高结合特异性、降低的脱靶效应以及在BTK变体中的强构象稳定性。该BTKi通过对BTK结合口袋进行结构优化来减轻脱靶效应，特别是在CYS481处，增强了结合特异性并减少了跨BTK突变体的非特异性相互作用。这些发现确立了该BTKi作为一种下一代BTKi，对自身免疫性和炎症性疾病，特别是MS具有增强的安全性和治疗潜力。
