title: Potent, selective, and orally bioavailable inhibitors of mammalian target of rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine.
abstract: A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i) < 1.0 nM and were highly (>100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States. fcohen@gene.com
authors.forename: Frederick
authors.initials: F
authors.lastname: Cohen
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: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Dipasquale
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Epler
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Ly
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Robarge
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: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005663:Furans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases