发现一类新型噻吩并嘧啶作为高效且选择性的PI3K抑制剂。
Discovery of a Novel Series of Thienopyrimidine as Highly Potent and Selective PI3K Inhibitors.
作者信息
Han Fangbin, Lin Songwen, Liu Peng, Liu Xiujie, Tao Jing, Deng Xiaobing, Yi Chongqin, Xu Heng
机构信息
PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
出版信息
ACS Med Chem Lett. 2015 Mar 11;6(4):434-8. doi: 10.1021/ml5005014. eCollection 2015 Apr 9.
Abstract
Inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway provides a promising new approach for cancer therapy. Through a rational design, a novel series of thienopyrimidine was discovered as highly potent and selective PI3K inhibitors. These thienopyrimidine derivatives were demonstrated to bear nanomolar PI3Kα inhibitory potency with over 100-fold selectivity against mTOR kinase. The lead compounds 6g and 6k showed good developability profiles in cell-based proliferation and ADME assays. In this communication, their design, synthesis, structure-activity relationship, selectivity, and some developability properties are described.
摘要
抑制磷酸肌醇3-激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路为癌症治疗提供了一种有前景的新方法。通过合理设计，发现了一系列新型噻吩并嘧啶作为高效且选择性的PI3K抑制剂。这些噻吩并嘧啶衍生物对PI3Kα具有纳摩尔级的抑制效力，对mTOR激酶的选择性超过100倍。先导化合物6g和6k在基于细胞的增殖和药物代谢动力学（ADME）试验中显示出良好的成药性。在本通讯中，描述了它们的设计、合成、构效关系、选择性以及一些成药性性质。
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