title: Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor.
abstract: 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 GI50 value 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Mingping
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Haojie
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Canhui
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: ylsong@smmu.edu.cn.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: zhuju@smmu.edu.cn.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C000614250:NSC765844; C546842:MTOR protein, human
keywords: Anticancer; Dual inhibitors; Mammalian target of rapamycin (mTOR); Phosphoinositide 3-kinase (PI3K)