title: Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy.
abstract: Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components. Cancer cells are thought to take advantage of autophagy to help them to cope with the stress of tumorigenesis; thus targeting autophagy is an attractive therapeutic approach. However, there are currently no specific inhibitors of autophagy. ULK1, a serine/threonine protein kinase, is essential for the initial stages of autophagy, and here we report that two compounds, MRT67307 and MRT68921, potently inhibit ULK1 and ULK2 in vitro and block autophagy in cells. Using a drug-resistant ULK1 mutant, we show that the autophagy-inhibiting capacity of the compounds is specifically through ULK1. ULK1 inhibition results in accumulation of stalled early autophagosomal structures, indicating a role for ULK1 in the maturation of autophagosomes as well as initiation.
authors.affiliation: From the Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland and.
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Petherick
authors.affiliation: From the Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland and.
authors.forename: Owen J L
authors.initials: OJ
authors.lastname: Conway
authors.affiliation: the MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom.
authors.forename: Chido
authors.initials: C
authors.lastname: Mpamhanga
authors.affiliation: the MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Osborne
authors.affiliation: the MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kamal
authors.affiliation: the MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Saxty
authors.affiliation: From the Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland and i.ganley@dundee.ac.uk.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Ganley
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse
keywords: ULK1; autophagy; cancer; cell biology; enzyme inhibitor; protein kinase; signal transduction
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