PMID- 31231029
OWN - NLM
STAT- MEDLINE
DCOM- 20200727
LR  - 20200727
IS  - 2451-9448 (Electronic)
IS  - 2451-9448 (Linking)
VI  - 26
IP  - 9
DP  - 2019 Sep 19
TI  - Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of 
      Glucose Transporters.
PG  - 1203-1213.e13
LID - S2451-9456(19)30178-3 [pii]
LID - 10.1016/j.chembiol.2019.05.009 [doi]
AB  - The mechanistic target of rapamycin (mTOR) is a central regulator of cellular 
      metabolic processes. Dysregulation of this kinase complex can result in a variety 
      of human diseases. Rapamycin and its analogs target mTORC1 directly; however, 
      chronic treatment in certain cell types and in vivo results in the inhibition of 
      both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for 
      the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 
      (Akt) substrates and have identified and characterized a chemical scaffold that 
      demonstrates a profile consistent with the selective inhibition of mTORC1. Stable 
      isotope labeling of amino acids in cell culture-based proteomic target 
      identification revealed that class I glucose transporters were the primary target 
      for these compounds yielding potent inhibition of glucose uptake and, as a 
      result, selective inhibition of mTORC1. The link between the glucose uptake and 
      selective mTORC1 inhibition are discussed in the context of a yet-to-be 
      discovered glucose sensor.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Kang, Seong A
AU  - Kang SA
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA. Electronic address: skang@navitorpharma.com.
FAU - O'Neill, David J
AU  - O'Neill DJ
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Machl, Andreas W
AU  - Machl AW
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Lumpkin, Casey J
AU  - Lumpkin CJ
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Galda, Stephanie N
AU  - Galda SN
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Sengupta, Shomit
AU  - Sengupta S
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Mahoney, Sarah J
AU  - Mahoney SJ
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Howell, Jessica J
AU  - Howell JJ
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Molz, Lisa
AU  - Molz L
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Hahm, Seung
AU  - Hahm S
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Vlasuk, George P
AU  - Vlasuk GP
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
FAU - Saiah, Eddine
AU  - Saiah E
AD  - Navitor Pharmaceuticals, Inc., 1030 Massachusetts Avenue, Suite 410, Cambridge, 
      MA 02138, USA.
LA  - eng
PT  - Journal Article
DEP - 20190620
PL  - United States
TA  - Cell Chem Biol
JT  - Cell chemical biology
JID - 101676030
RN  - 0 (Glucose Transport Proteins, Facilitative)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Transcription Factors)
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 (Proto-Oncogene Proteins c-akt)
RN  - IY9XDZ35W2 (Glucose)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cell Chem Biol. 2019 Sep 19;26(9):1195-1196. PMID: 31539502
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Evaluation, Preclinical/methods
MH  - Glucose/metabolism
MH  - Glucose Transport Proteins, Facilitative/*drug effects
MH  - High-Throughput Screening Assays/methods
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiprotein Complexes/metabolism
MH  - Phosphorylation
MH  - Proteomics/methods
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/analogs & derivatives/metabolism/*pharmacology
MH  - Transcription Factors/metabolism
OTO - NOTNLM
OT  - 4E-BP1
OT  - Akt
OT  - GLUT
OT  - GLUT1
OT  - S6K1
OT  - mTOR
OT  - mTORC1
OT  - pharmacological inhibition
OT  - rapalog
OT  - rapamycin
EDAT- 2019/06/25 06:00
MHDA- 2020/07/28 06:00
CRDT- 2019/06/25 06:00
PHST- 2019/01/17 00:00 [received]
PHST- 2019/04/12 00:00 [revised]
PHST- 2019/05/22 00:00 [accepted]
PHST- 2019/06/25 06:00 [pubmed]
PHST- 2020/07/28 06:00 [medline]
PHST- 2019/06/25 06:00 [entrez]
AID - S2451-9456(19)30178-3 [pii]
AID - 10.1016/j.chembiol.2019.05.009 [doi]
PST - ppublish
SO  - Cell Chem Biol. 2019 Sep 19;26(9):1203-1213.e13. doi: 
      10.1016/j.chembiol.2019.05.009. Epub 2019 Jun 20.