Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy

Katy J. Petherick, Owen J. L. Conway, Chido Mpamhanga, Simon A. Osborne, Ahmad Kamal, Barbara Saxty, Ian G. Ganley (Lead / Corresponding author)

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    134 Citations (Scopus)
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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 2 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.

    Original languageEnglish
    Pages (from-to)11376-11383
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume290
    Issue number18
    Early online date1 Apr 2015
    DOIs
    Publication statusPublished - 1 May 2015

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