title: Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors.
abstract: Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. dangelo@amgen.com
authors.forename: Noel D
authors.initials: ND
authors.lastname: D'Angelo
authors.forename: Tae-Seong
authors.initials: TS
authors.lastname: Kim
authors.forename: Kristin
authors.initials: K
authors.lastname: Andrews
authors.forename: Shon K
authors.initials: SK
authors.lastname: Booker
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Derin
authors.initials: D
authors.lastname: D'Amico
authors.forename: Dan
authors.initials: D
authors.lastname: Freeman
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.forename: Longbin
authors.initials: L
authors.lastname: Liu
authors.forename: John D
authors.initials: JD
authors.lastname: McCarter
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mullady
authors.forename: Michael
authors.initials: M
authors.lastname: Schrag
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.forename: Jin
authors.initials: J
authors.lastname: Tang
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Tian
authors.initials: T
authors.lastname: Wu
authors.forename: Ning
authors.initials: N
authors.lastname: Xi
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Peter
authors.initials: P
authors.lastname: Yakowec
authors.forename: Kevin
authors.initials: K
authors.lastname: Yang
authors.forename: Leeanne P
authors.initials: LP
authors.lastname: Zalameda
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Paul
authors.initials: P
authors.lastname: Hughes
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C558744:N-(6-(6-chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo(d)thiazol-2-yl)acetamide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases