1086062-75-0Relevant articles and documents
Identification of 3-amidoquinoline derivatives as PI3K/mTOR dual inhibitors with potential for cancer therapy
Zhang, Jiankang,Ma, Xiaodong,Lv, Xiaoqing,Li, Ming,Zhao, Yanmei,Liu, Guoqiang,Zhan, Shuyu
, p. 2342 - 2350 (2017)
A new series of 3-amidoquinoline derivatives were designed, synthesized and evaluated as PI3K/mTOR dual inhibitors. Among them, five compounds showed potent PI3Kα inhibitory activities (IC50 50 1 μM). The representative compound 15a can significantly inhibit other class I PI3Ks, mTOR and phosphorylation of pAkt(Ser473) at low nanomolar level, suggesting that 15a was a potent PI3K/mTOR dual inhibitor. Moreover, 15a displayed favorable pharmacokinetic properties in vivo.
Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor
Han, Jinsong,Chen, Ying,Yang, Chao,Liu, Ting,Wang, Mingping,Xu, Haojie,Zhang, Ling,Zheng, Canhui,Song, Yunlong,Zhu, Ju
, p. 684 - 701 (2016/07/21)
The phosphoinositide 3-kinase (PI3K) family is one of the most frequently activated enzymes in a wide range of human cancers; thus, inhibition of PI3K represents a promising strategy for cancer therapy. Herein, a series of benzylamine substituted arylsulfonamides were designed and synthesized as dual PI3K/mTOR inhibitors using a strategy integrating focused library design and virtual screening, resulting in the discovery of 13b (NSC765844). The compound 13b exhibits highly potent enzyme inhibition with IC50s of 1.3, 1.8, 1.5, 3.8 and 3.8?nM for PI3Kα, β, γ, δ, and mTOR, respectively. 13b was further evaluated in NCI by an in?vitro cytotoxic screening program. Broad-spectrum antitumor activities with mean GI50value of 18.6?nM against approximately 60 human tumor cell lines were found. 13b displayed favorable physicochemical properties and superior pharmacokinetic profiles for animal studies. It significantly inhibited tumor growth when administered orally in an A549 non-small-cell lung carcinoma xenograft and BEL7404 human hepatocellular carcinoma xenograft models. On the basis of its excellent in?vivo efficacy and superior pharmacokinetic profiles, 13b has been selected for further preclinical investigation as a promising anticancer drug candidate.
PI3 KINASE MODULATORS AND METHODS OF USE
-
, (2014/02/16)
This invention relates to the field of lipid kinases and modulators thereof. In particular, the invention relates to modulators of phosphatidylinositol 3-kinases (PI3 kinases or PBKs) signaling pathways, and methods of their use. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in modulating of PI3K signaling pathways and their related disorders in mammals, especially humans.
