PMID- 19402821
OWN - NLM
STAT- MEDLINE
DCOM- 20090715
LR  - 20231120
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 421
IP  - 1
DP  - 2009 Jun 12
TI  - Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR).
PG  - 29-42
LID - 10.1042/BJ20090489 [doi]
AB  - mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating 
      and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase 
      C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) 
      and SGK (serum and glucocorticoid protein kinase). mTORC1 (mTOR complex-1) 
      phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the 
      hydrophobic motif of Akt and SGK. In the present paper we describe the small 
      molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of 
      approximately 10 nM, but does not suppress the activity of 76 other protein 
      kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 
      3-kinases) at 1000-fold higher concentrations. Ku-0063794 is cell permeant, 
      suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, 
      but not RSK (ribosomal S6 kinase), an AGC kinase not regulated by mTOR. 
      Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt 
      phosphorylated by PDK1 (3-phosphoinositide-dependent protein kinase-1). We 
      interpret this as implying phosphorylation of Ser473 promotes phosphorylation of 
      Thr308 and/or induces a conformational change that protects Thr308 from 
      dephosphorylation. In contrast, Ku-0063794 does not affect Thr308 phosphorylation 
      in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling 
      processes have adapted to enable Thr308 phosphorylation to occur in the absence 
      of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater 
      dephosphorylation of the mTORC1 substrate 4E-BP1 (eukaryotic initiation factor 
      4E-binding protein 1) than rapamycin, even in mTORC2-deficient cells, suggesting 
      a form of mTOR distinct from mTORC1, or mTORC2 phosphorylates 4E-BP1. Ku-0063794 
      also suppressed cell growth and induced a G1-cell-cycle arrest. Our results 
      indicate that Ku-0063794 will be useful in delineating the physiological roles of 
      mTOR and may have utility in treatment of cancers in which this pathway is 
      inappropriately activated.
FAU - Garcia-Martinez, Juan M
AU  - Garcia-Martinez JM
AD  - MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, 
      Dow Street, Dundee DD15EH, Scotland, UK.
FAU - Moran, Jennifer
AU  - Moran J
FAU - Clarke, Rosemary G
AU  - Clarke RG
FAU - Gray, Alex
AU  - Gray A
FAU - Cosulich, Sabina C
AU  - Cosulich SC
FAU - Chresta, Christine M
AU  - Chresta CM
FAU - Alessi, Dario R
AU  - Alessi DR
LA  - eng
GR  - G9403619/MRC_/Medical Research Council/United Kingdom
GR  - MC_U127015387/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090612
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Morpholines)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Pyrimidines)
RN  - 0 (Transcription Factors)
RN  - 81HJG228AB (Ku 0063794)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Fibroblasts/drug effects/metabolism
MH  - G1 Phase/drug effects
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation/*drug effects
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Morpholines/*chemistry/*pharmacology
MH  - Multiprotein Complexes
MH  - Proteins
MH  - Pyrimidines/*chemistry/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*antagonists & inhibitors/metabolism
PMC - PMC2708931
EDAT- 2009/05/01 09:00
MHDA- 2009/07/16 09:00
PMCR- 2009/06/12
CRDT- 2009/05/01 09:00
PHST- 2009/05/01 09:00 [entrez]
PHST- 2009/05/01 09:00 [pubmed]
PHST- 2009/07/16 09:00 [medline]
PHST- 2009/06/12 00:00 [pmc-release]
AID - BJ20090489 [pii]
AID - bj4210029 [pii]
AID - 10.1042/BJ20090489 [doi]
PST - epublish
SO  - Biochem J. 2009 Jun 12;421(1):29-42. doi: 10.1042/BJ20090489.