Department of Pharmacy, Shaanxi University of Science & Technology, Xi'an, 710021, PR China.
Department of Pharmacy, Shaanxi University of Science & Technology, Xi'an, 710021, PR China.
Eur J Med Chem. 2018 May 10;151:315-326. doi: 10.1016/j.ejmech.2018.03.062. Epub 2018 Mar 23.
Bruton's tyrosine kinase (BTK) has emerged as a promising drug target for multiple diseases, particularly haematopoietic malignancies and autoimmune diseases related to B lymphocytes. This review focuses on the diverse, small-molecule inhibitors of BTK kinase that have shown good prospects for clinical application. Individual examples of these inhibitors, including both reversible and irreversible inhibitors and a recently developed reversible covalent inhibitor of BTK, are discussed. Considerable progress has been made in the development of irreversible inhibitors, most of which target the SH3 pocket and the cysteine 481 residue of BTK. The present review also surveys the pharmacological advantages and deficiencies of both reversible and irreversible BTK drugs, with a focus on the structure-activity relationship (SARs) and binding modes of representative drugs, which could inspire critical thinking and new ideas for developing potent BTK inhibitors with less unwanted off-target effects.
布鲁顿酪氨酸激酶（BTK）已成为多种疾病的有前途的药物靶点，特别是与 B 淋巴细胞相关的血液恶性肿瘤和自身免疫性疾病。本综述重点介绍了具有良好临床应用前景的 BTK 激酶的多种小分子抑制剂。讨论了这些抑制剂的个别例子，包括可逆和不可逆抑制剂，以及最近开发的 BTK 的可逆共价抑制剂。在不可逆抑制剂的开发方面取得了相当大的进展，其中大多数靶向 BTK 的 SH3 口袋和半胱氨酸 481 残基。本综述还调查了可逆和不可逆 BTK 药物的药理学优势和缺陷，重点是代表性药物的结构-活性关系（SAR）和结合模式，这可能为开发具有较少非靶标副作用的有效 BTK 抑制剂提供批判性思维和新想法。
