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Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.
- Source :
-
Molecular cell [Mol Cell] 2015 Jul 16; Vol. 59 (2), pp. 285-97. Date of Electronic Publication: 2015 Jun 25. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Animals
Autophagy drug effects
Autophagy-Related Protein-1 Homolog
Benzamides chemistry
Catalytic Domain genetics
Cell Survival drug effects
Cell Survival physiology
Cells, Cultured
Consensus Sequence
Gene Knockout Techniques
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins genetics
Mice
Molecular Sequence Data
Phosphorylation
Protein Kinase Inhibitors chemistry
Protein Serine-Threonine Kinases deficiency
Protein Serine-Threonine Kinases genetics
Pyrimidines chemistry
RNA, Small Interfering genetics
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins metabolism
Substrate Specificity
Autophagy physiology
Benzamides pharmacology
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Intracellular Signaling Peptides and Proteins metabolism
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Serine-Threonine Kinases metabolism
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 59
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 26118643
- Full Text :
- https://doi.org/10.1016/j.molcel.2015.05.031