一种高活性高选择性TypeⅡ不可逆BMX激酶抑制剂的开发
发布时间：2018-11-23 06:34
【摘要】：BMX激酶是第二大非受体酪氨酸激酶TEC家族中的一员,生物学研究表明BMX激酶参与多种重要的生理和病理过程。目前已知的靶向BMX激酶的小分子抑制剂较少且多数为多靶点化合物,由于BMX激酶所介导信号通路的具体机制仍不是很明确,因此极需高活性、高选择性的BMX激酶抑制剂用于相关作用机制的研究和药物功效的概念性验证。基于BMX激酶的晶体结构,整合了 Type II激酶抑制剂和不可逆激酶抑制剂的两种设计理念,我们研发出一种高选择性、高活性的Type Ⅱ不可逆BMX激酶抑制剂化合物41(CHMFL-BMX-078)。该化合物与BMX激酶的非活化构型相结合,同时与BMX激酶的Cys496残基的侧链形成不可逆的共价键结合。化合物41不仅在激酶组(468种)检测中表现出很高的选择性,更重要的是在与BMX激酶结构相近的BTK、JAK3、EGFR和MAP2K7激酶中取得了选择性。该抑制剂对于BMX激酶的抑制活性(IC50)为llnM,同时对BaF3-TEL-BMX细胞增殖的抑制活性(GI50)为16nM。该抑制剂的发现为深入探究BMX激酶所介导的信号通路在生理、病理环境中的作用机制提供了新的药理学研究工具。
[Abstract]:BMX kinase is a member of the second largest non-receptor tyrosine kinase TEC family. Biological studies have shown that BMX kinase is involved in many important physiological and pathological processes. At present, the known small molecular inhibitors of BMX kinase are few and most of them are multi-target compounds. Because the specific mechanism of signal pathway mediated by BMX kinase is still not clear, it is very necessary to have high activity. Highly selective BMX kinase inhibitors are used in the study of related mechanisms and in conceptual validation of drug efficacy. Based on the crystal structure of BMX kinase and two design concepts of Type II kinase inhibitor and irreversible kinase inhibitor, we developed a highly selective and highly active Type 鈪，
本文编号：2350630
[Abstract]:BMX kinase is a member of the second largest non-receptor tyrosine kinase TEC family. Biological studies have shown that BMX kinase is involved in many important physiological and pathological processes. At present, the known small molecular inhibitors of BMX kinase are few and most of them are multi-target compounds. Because the specific mechanism of signal pathway mediated by BMX kinase is still not clear, it is very necessary to have high activity. Highly selective BMX kinase inhibitors are used in the study of related mechanisms and in conceptual validation of drug efficacy. Based on the crystal structure of BMX kinase and two design concepts of Type II kinase inhibitor and irreversible kinase inhibitor, we developed a highly selective and highly active Type 鈪，
本文编号：2350630
本文链接：https://www.wllwen.com/shoufeilunwen/boshibiyelunwen/2350630.html
