PMID- 23199076
OWN - NLM
STAT- MEDLINE
DCOM- 20130314
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 55
IP  - 24
DP  - 2012 Dec 27
TI  - Potent, selective, and orally bioavailable inhibitors of the mammalian target of 
      rapamycin kinase domain exhibiting single agent antiproliferative activity.
PG  - 10958-71
LID - 10.1021/jm301389h [doi]
AB  - 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.
FAU - Koehler, Michael F T
AU  - Koehler MF
AD  - Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San 
      Francisco, California 94080, USA. mkoehler@gene.com
FAU - Bergeron, Philippe
AU  - Bergeron P
FAU - Blackwood, Elizabeth
AU  - Blackwood E
FAU - Bowman, Krista K
AU  - Bowman KK
FAU - Chen, Yung-Hsiang
AU  - Chen YH
FAU - Deshmukh, Gauri
AU  - Deshmukh G
FAU - Ding, Xiao
AU  - Ding X
FAU - Epler, Jennifer
AU  - Epler J
FAU - Lau, Kevin
AU  - Lau K
FAU - Lee, Leslie
AU  - Lee L
FAU - Liu, Lichuan
AU  - Liu L
FAU - Ly, Cuong
AU  - Ly C
FAU - Malek, Shiva
AU  - Malek S
FAU - Nonomiya, Jim
AU  - Nonomiya J
FAU - Oeh, Jason
AU  - Oeh J
FAU - Ortwine, Daniel F
AU  - Ortwine DF
FAU - Sampath, Deepak
AU  - Sampath D
FAU - Sideris, Steve
AU  - Sideris S
FAU - Trinh, Lan
AU  - Trinh L
FAU - Truong, Tom
AU  - Truong T
FAU - Wu, Jiansheng
AU  - Wu J
FAU - Pei, Zhonghua
AU  - Pei Z
FAU - Lyssikatos, Joseph P
AU  - Lyssikatos JP
LA  - eng
PT  - Journal Article
DEP - 20121212
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 0 (Quinazolines)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology
MH  - Biological Availability
MH  - Cell Line, Tumor
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - Humans
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mice, Nude
MH  - Molecular Docking Simulation
MH  - Multiprotein Complexes/*antagonists & inhibitors
MH  - Neoplasm Transplantation
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Prostatic Neoplasms
MH  - Pyrimidines/*chemical synthesis/chemistry/pharmacology
MH  - Pyrroles/*chemical synthesis/chemistry/pharmacology
MH  - Quinazolines/*chemical synthesis/chemistry/pharmacology
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Transplantation, Heterologous
EDAT- 2012/12/04 06:00
MHDA- 2013/03/15 06:00
CRDT- 2012/12/04 06:00
PHST- 2012/12/04 06:00 [entrez]
PHST- 2012/12/04 06:00 [pubmed]
PHST- 2013/03/15 06:00 [medline]
AID - 10.1021/jm301389h [doi]
PST - ppublish
SO  - J Med Chem. 2012 Dec 27;55(24):10958-71. doi: 10.1021/jm301389h. Epub 2012 Dec 
      12.