title: Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349.
abstract: Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Frederick
authors.initials: F
authors.lastname: Cohen
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bergeron
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Cuong
authors.initials: C
authors.lastname: Ly
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Epler
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Bao
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ulka
authors.initials: U
authors.lastname: Vijapurkar
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mukadam
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
keywords: Mammalian target of rapamycin; TDI; mTOR; urea bioisostere