PMID- 26118643
OWN - NLM
STAT- MEDLINE
DCOM- 20151014
LR  - 20220408
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 59
IP  - 2
DP  - 2015 Jul 16
TI  - Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 
      Substrates.
PG  - 285-97
LID - S1097-2765(15)00398-6 [pii]
LID - 10.1016/j.molcel.2015.05.031 [doi]
AB  - Many tumors become addicted to autophagy for survival, suggesting inhibition of 
      autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only 
      serine/threonine kinase in the core autophagy pathway and thus represents an 
      excellent drug target. Despite recent advances in the understanding of ULK1 
      activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly 
      understood. Here, we screened degenerate peptide libraries to deduce the optimal 
      ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy 
      proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 
      substrates to perform a cell-based screen to identify and characterize a potent 
      ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective 
      ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation 
      events in cells, regulating autophagy and cell survival. SBI-0206965 greatly 
      synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor 
      cells, providing a strong rationale for their combined use in the clinic.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Egan, Daniel F
AU  - Egan DF
AD  - Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 
      La Jolla, CA 92037, USA.
FAU - Chun, Matthew G H
AU  - Chun MG
AD  - Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 
      La Jolla, CA 92037, USA.
FAU - Vamos, Mitchell
AU  - Vamos M
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Zou, Haixia
AU  - Zou H
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Rong, Juan
AU  - Rong J
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Miller, Chad J
AU  - Miller CJ
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA.
FAU - Lou, Hua Jane
AU  - Lou HJ
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA.
FAU - Raveendra-Panickar, Dhanya
AU  - Raveendra-Panickar D
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Yang, Chih-Cheng
AU  - Yang CC
AD  - Functional Genomics Core, Sanford-Burnham Medical Research Institute, 10901 North 
      Torrey Pines Road, La Jolla, CA 92037, USA.
FAU - Sheffler, Douglas J
AU  - Sheffler DJ
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Teriete, Peter
AU  - Teriete P
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA.
FAU - Asara, John M
AU  - Asara JM
AD  - Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 
      02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, 
      USA.
FAU - Turk, Benjamin E
AU  - Turk BE
AD  - Department of Pharmacology, Yale University School of Medicine, New Haven, CT 
      06520, USA.
FAU - Cosford, Nicholas D P
AU  - Cosford ND
AD  - Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, 
      Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La 
      Jolla, CA 92037, USA. Electronic address: ncosford@sanfordburnham.org.
FAU - Shaw, Reuben J
AU  - Shaw RJ
AD  - Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 
      La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for 
      Biological Studies, La Jolla, CA 92037, USA. Electronic address: shaw@salk.edu.
LA  - eng
GR  - R01CA172229/CA/NCI NIH HHS/United States
GR  - T32 GM007324/GM/NIGMS NIH HHS/United States
GR  - R01 GM104047/GM/NIGMS NIH HHS/United States
GR  - R01CA188694/CA/NCI NIH HHS/United States
GR  - P30 CA014195/CA/NCI NIH HHS/United States
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - R01 CA172229/CA/NCI NIH HHS/United States
GR  - T32 GM007240/GM/NIGMS NIH HHS/United States
GR  - P30 CA030199/CA/NCI NIH HHS/United States
GR  - R01GM104047/GM/NIGMS NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 CA188694/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150625
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Benzamides)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Recombinant Proteins)
RN  - 0 (SBI-0206965)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ULK1 protein, human)
RN  - EC 2.7.11.1 (Ulk1 protein, mouse)
SB  - IM
CIN - Nat Chem Biol. 2015 Oct;11(10):758-60. PMID: 26379023
MH  - Amino Acid Sequence
MH  - Animals
MH  - Autophagy/drug effects/*physiology
MH  - Autophagy-Related Protein-1 Homolog
MH  - Benzamides/chemistry/*pharmacology
MH  - Catalytic Domain/genetics
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Consensus Sequence
MH  - Gene Knockout Techniques
MH  - HEK293 Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*antagonists & 
      inhibitors/genetics/*metabolism
MH  - Mice
MH  - Molecular Sequence Data
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/chemistry/*pharmacology
MH  - Protein Serine-Threonine Kinases/*antagonists & 
      inhibitors/deficiency/genetics/*metabolism
MH  - Pyrimidines/chemistry/*pharmacology
MH  - RNA, Small Interfering/genetics
MH  - Recombinant Proteins/chemistry/genetics/metabolism
MH  - Substrate Specificity
PMC - PMC4530630
MID - NIHMS705486
EDAT- 2015/06/30 06:00
MHDA- 2015/10/16 06:00
PMCR- 2016/07/16
CRDT- 2015/06/30 06:00
PHST- 2015/03/30 00:00 [received]
PHST- 2015/05/17 00:00 [revised]
PHST- 2015/05/22 00:00 [accepted]
PHST- 2015/06/30 06:00 [entrez]
PHST- 2015/06/30 06:00 [pubmed]
PHST- 2015/10/16 06:00 [medline]
PHST- 2016/07/16 00:00 [pmc-release]
AID - S1097-2765(15)00398-6 [pii]
AID - 10.1016/j.molcel.2015.05.031 [doi]
PST - ppublish
SO  - Mol Cell. 2015 Jul 16;59(2):285-97. doi: 10.1016/j.molcel.2015.05.031. Epub 2015 
      Jun 25.