Department of Chemistry, College of Sciences and Health Professions, Cleveland State University , 2121 Euclid Avenue, Cleveland, Ohio 44115, United States.
J Med Chem. 2013 Jul 11;56(13):5306-20. doi: 10.1021/jm4004736. Epub 2013 Jun 28.
Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.
热休克蛋白 27（Hsp27）是一种伴侣蛋白，其表达水平会因各种应激刺激而增加，包括抗癌化疗，这使细胞能够存活并产生耐药性。我们之前通过蛋白质组学方法鉴定了与 Hsp27 和微管蛋白结合的先导化合物。在本研究中，系统的基于配体的优化显著提高了化合物对细胞生长的抑制和诱导凋亡的活性。与先导化合物相比，新衍生物中的一种对微管蛋白聚合的抑制活性大大提高，但对抑制 Hsp27 伴侣功能的活性降低，表明结构修饰分离了化合物的双重靶向作用。最有效的化合物 20 和 22 在亚纳摩尔浓度下对国立癌症研究所发育治疗计划进行的 60 个人类癌细胞系表现出强烈的细胞增殖抑制活性，代表了有希望的抗癌药物开发候选物。
