發(fā)布時(shí)間：2018-11-23 06:34

【摘要】：BMX激酶是第二大非受體酪氨酸激酶TEC家族中的一員,生物學(xué)研究表明BMX激酶參與多種重要的生理和病理過(guò)程。目前已知的靶向BMX激酶的小分子抑制劑較少且多數(shù)為多靶點(diǎn)化合物,由于BMX激酶所介導(dǎo)信號(hào)通路的具體機(jī)制仍不是很明確,因此極需高活性、高選擇性的BMX激酶抑制劑用于相關(guān)作用機(jī)制的研究和藥物功效的概念性驗(yàn)證�；�于BMX激酶的晶體結(jié)構(gòu),整合了 Type II激酶抑制劑和不可逆激酶抑制劑的兩種設(shè)計(jì)理念,我們研發(fā)出一種高選擇性、高活性的Type Ⅱ不可逆BMX激酶抑制劑化合物41(CHMFL-BMX-078)。該化合物與BMX激酶的非活化構(gòu)型相結(jié)合,同時(shí)與BMX激酶的Cys496殘基的側(cè)鏈形成不可逆的共價(jià)鍵結(jié)合�；�合物41不僅在激酶組(468種)檢測(cè)中表現(xiàn)出很高的選擇性,更重要的是在與BMX激酶結(jié)構(gòu)相近的BTK、JAK3、EGFR和MAP2K7激酶中取得了選擇性。該抑制劑對(duì)于BMX激酶的抑制活性(IC50)為llnM,同時(shí)對(duì)BaF3-TEL-BMX細(xì)胞增殖的抑制活性(GI50)為16nM。該抑制劑的發(fā)現(xiàn)為深入探究BMX激酶所介導(dǎo)的信號(hào)通路在生理、病理環(huán)境中的作用機(jī)制提供了新的藥理學(xué)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，

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