Structure of the Human Autophagy Initiating Kinase ULK1 in Complex with Potent Inhibitors

• Published in: ACS chemical biology Vol. 10; no. 1; pp. 257 - 261
• Main Authors: Lazarus, Michael B, Novotny, Chris J, Shokat, Kevan M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.01.2015
• Subjects: Autophagy - drug effects; Autophagy - physiology; Autophagy-Related Protein-1 Homolog; Escherichia coli - genetics; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Letters; Models, Molecular; Protein Binding; Protein Conformation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 1554-8929; 1554-8937; 1554-8937
• DOI: 10.1021/cb500835z

Autophagy is a conserved cellular process that involves the degradation of cellular components for energy maintenance and cytoplasmic quality control that has recently gained interest as a novel target for a variety of human diseases, including cancer. A prime candidate to determine the potential therapeutic benefit of targeting autophagy is the kinase ULK1, whose activation initiates autophagy. Here, we report the first structures of ULK1, in complex with multiple potent inhibitors. These structures show features unique to the enzyme and will provide a path for the rational design of selective compounds as cellular probes and potential therapeutics.