【作者】 孟韬； 马兰萍； 于霆； 王昕； 余科； 沈竞康；

【Author】 MENG Tao;MA Lan-ping;YU Ting;WANG Xin;YU Ke;SHEN Jing-kang;Shanghai Institute of Materia Medica;Fudan University,School of Pharmacy;

【机构】 中国科学院上海药物研究所； 复旦大学药学院；

【摘要】 目的雷帕霉素靶蛋白mTOR信号通路是调控细胞生长的一个关键通路,mTOR信号通路的异常激活是多种人类重大疾病发生和发展的共性。通过分析现有药物市场,以及技术风险等多个因素,我们研究团队在已报道的化合物的基础上,经合理设计,综合考虑前期研究中药物的有效性、安全性及化合物的水溶性、代谢稳定性等因素,得到的一类新型的、口服有效的ATP竞争性mTOR选择性抑制剂。结果其中化合物SCC-31的体内外活性与I/II期临床类似物AZD2014相当(IC₅₀=0.039±0.001μM,最低口服有效剂量约为5 mg/kg/day),化合物种属差异性较小,口服暴露量高,且小鼠体内2周毒性试验较之临床化合物AZD8055与AZD2014有更好的安全性。结论经初步临床前研究后,SCC-31有望开发成为制备简便、活性更高的抗肿瘤药物。更多还原

【Abstract】 OBJECTIVE Mammalian target of rapamycin(mTOR) signaling pathway is a key pathway regulating cell growth,abnormal activation of mTOR signaling pathway is a variety of major diseases and the development of human commonality.METHODS By analyzing a number of factors existing drug market,and technical risk,on the basis of rational design,considering the validity of previous studies of water-solubility,safety and metabolic stability and other factors to give a new class of orally active selective ATP-competitive inhibitors of mTOR.Compounds SCC-31 results in vitro and in vivo activity of IC50 = 0.039 ± 0.001 μ M,the lowest effective oral dose of about 5 mg / kg / day,this compound showed mininal species differences,oral exposure level as well as better safety window in the two weeks toxicity test compare to the clinical compound AZD8055 or AZD2014.CONCLUSION After initial preclinical studies,SCC-31 is expected to be developed into the easy prepared and potent anticancer drugs.更多还原