title: Discovery of a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as PI3K/mTOR dual inhibitors.
abstract: Recently, the phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been considered as promising targets for the treatment of cancer. Herein, we synthesized a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as novel PI3K/mTOR dual inhibitors for cancer therapy. In the biological evaluation, compound 17e was identified as a potent PI3K/mTOR dual inhibitor, which significantly inhibit Class I PI3Ks, mTOR and phosphorylation of pAkt(Ser473) at low nanomolar level. Moreover, 17e display high potency against PC-3 cells (IC50= 80 nM) in the anti-proliferative assay, and showed acceptable pharmacokinetic properties in vivo.
authors.affiliation: Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Medicine, Jiaxing University, Jiaxing 314001, China. Electronic address: lxqd1@126.com.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230031, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D000096926:Benzenesulfonamides
keywords: Cancer; Inhibitor; PI3K; mTOR