Han Fangbin, Lin Songwen, Liu Peng, Liu Xiujie, Tao Jing, Deng Xiaobing, Yi Chongqin, Xu Heng
PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
ACS Med Chem Lett. 2015 Mar 11;6(4):434-8. doi: 10.1021/ml5005014. eCollection 2015 Apr 9.
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.
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。
