Pharmacological Inhibition of ULK1 Blocks mTOR-Dependent Autophagy [Cell Biology]

April 1st, 2015 by Petherick, K. J., Conway, O. J. L., Mpamhanga, C., Osborne, S. A., Kamal, A., Saxty, B., Ganley, I. G.

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.