Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (mTOR)-dependent Autophagy |
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| Authors: | Katy J Petherick Owen J L Conway Chido Mpamhanga Simon A Osborne Ahmad Kamal Barbara Saxty Ian G Ganley |
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| Institution: | From the ‡Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland and ;the §MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom |
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| 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. |
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| Keywords: | autophagy cell biology enzyme inhibitor protein kinase signal transduction ULK1 cancer |
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