2. Academic Validation
  3. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates

Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates

  • Mol Cell. 2015 Jul 16;59(2):285-97. doi: 10.1016/j.molcel.2015.05.031.
Daniel F Egan 1,  Matthew G H Chun 1,  Mitchell Vamos 2,  Haixia Zou 2,  Juan Rong 2,  Chad J Miller 3,  Hua Jane Lou 3,  Dhanya Raveendra-Panickar 2,  Chih-Cheng Yang 4,  Douglas J Sheffler 2,  Peter Teriete 2,  John M Asara 5,  Benjamin E Turk 3,  Nicholas D P Cosford 6,  Reuben J Shaw 7
Affiliations

Affiliations

  • 1 Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 2 Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 3 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 4 Functional Genomics Core, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 5 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: ncosford@sanfordburnham.org.
  • 7 Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: shaw@salk.edu.
PMID: 26118643 DOI: 10.1016/j.molcel.2015.05.031
Abstract

Many tumors become addicted to Autophagy for survival, suggesting inhibition of Autophagy as a potential broadly applicable Cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core Autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes Autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core Autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating Autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.

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