Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (mTOR)-dependent Autophagy

• DOI: 10.1074/jbc.c114.627778
• Publication Date: 2015-04-02T15:55:55Z
• Authors: Katy J. Petherick; Owen J.L. Conway; Chido Mpamhanga; Simon A. Osborne; Ahmad Kamal; Barbara Saxty; Ian G. Ganley
• Keywords: ULK1; Autophagosome; BAG3; Autophagy-related protein 13

Autophagy is a cell-protective and degradative process that recycles damaged long-lived cellular components. Cancer cells are thought to take advantage of autophagy help them cope with the stress tumorigenesis; thus targeting an attractive therapeutic approach. However, there currently no specific inhibitors autophagy. ULK1, serine/threonine protein kinase, essential for initial stages autophagy, here we report two compounds, MRT67307 MRT68921, potently inhibit ULK1 ULK2 in vitro block cells. Using drug-resistant mutant, show autophagy-inhibiting capacity compounds specifically through ULK1. inhibition results accumulation stalled early autophagosomal structures, indicating role maturation autophagosomes as well initiation.