Wang Lin, Zhang Zhengjie, Yu Dongke, Yang Liuqing, Li Ling, He Yuxin, Shi Jianyou
College of Food and Bioengineering, Xihua University, Chengdu 610039, China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China.
Bioorg Chem. 2023 Sep;138:106577. doi: 10.1016/j.bioorg.2023.106577. Epub 2023 May 2.
Protein kinases constitute the largest group within the kinase family, and mutations and translocations of protein kinases due to genetic alterations are intimately linked to the pathogenesis of numerous diseases. Bruton's tyrosine kinase (BTK) is a member of the protein kinases and plays a pivotal role in the development and function of B cells. BTK belongs to the tyrosine TEC family. The aberrant activation of BTK is closely associated with the pathogenesis of B-cell lymphoma. Consequently, BTK has always been a critical target for treating hematological malignancies. To date, two generations of small-molecule covalent irreversible BTK inhibitors have been employed to treat malignant B-cell tumors, and have exhibited clinical efficacy in hitherto refractory diseases. However, these drugs are covalent BTK inhibitors, which inevitably lead to drug resistance after prolonged use, resulting in poor tolerance in patients. The third-generation non-covalent BTK inhibitor Pirtobrutinib has obtained approval for marketing in the United States, thereby circumventing drug resistance caused by C481 mutation. Currently, enhancing safety and tolerance constitutes the primary issue in developing novel BTK inhibitors. This article systematically summarizes recently discovered covalent and non-covalent BTK inhibitors and classifies them according to their structures. This article also provides a detailed discussion of binding modes, structural features, pharmacological activities, advantages and limitations of typical compounds within each structure type, providing valuable references and insights for developing safer, more effective and more targeted BTK inhibitors in future studies.
蛋白激酶是激酶家族中最大的一类，由于基因改变导致的蛋白激酶突变和易位与多种疾病的发病机制密切相关。布鲁顿酪氨酸激酶（BTK）是蛋白激酶家族的一员，在B细胞的发育和功能中起关键作用。BTK属于酪氨酸TEC家族。BTK的异常激活与B细胞淋巴瘤的发病机制密切相关。因此，BTK一直是治疗血液系统恶性肿瘤的关键靶点。迄今为止，两代小分子共价不可逆BTK抑制剂已被用于治疗恶性B细胞肿瘤，并在迄今难治的疾病中显示出临床疗效。然而，这些药物是共价BTK抑制剂，长期使用后不可避免地会导致耐药性，导致患者耐受性差。第三代非共价BTK抑制剂 pirtobrutinib已在美国获得上市批准，从而规避了由C481突变引起的耐药性。目前，提高安全性和耐受性是开发新型BTK抑制剂的首要问题。本文系统总结了最近发现的共价和非共价BTK抑制剂，并根据其结构进行分类。本文还详细讨论了每种结构类型中典型化合物的结合模式、结构特征、药理活性、优点和局限性，为未来研究开发更安全、更有效、更具针对性的BTK抑制剂提供了有价值的参考和见解。
