title: Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity.
abstract: Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i) < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. mkoehler@gene.com
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.forename: Philippe
authors.initials: P
authors.lastname: Bergeron
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Jennifer
authors.initials: J
authors.lastname: Epler
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.forename: Cuong
authors.initials: C
authors.lastname: Ly
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases