Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1

Michael B. Lazarus, Kevan M. Shokat

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Energy homeostasis in eukaryotic cells is a complex and fundamental process that is misregulated in several human diseases. A key component of energy regulation is a process called autophagy that involves the recycling of cellular components. There has been much recent interest in studying the mechanism of autophagy to understand an important cellular process and to evaluate the therapeutic potential in targeting autophagy. Activation of a kinase called ULK1 initiates autophagy by driving downstream pathways that lead to the formation of double membrane bound vesicles that surround the cellular contents that are to be degraded. Here, we report the discovery of an inhibitor of ULK1 with improved selectivity and a high-resolution crystal structure of the compound bound to the kinase, which will be useful tools for studying autophagy in cells.

Original languageEnglish
Pages (from-to)5483-5488
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number17
DOIs
StatePublished - 1 Sep 2015
Externally publishedYes

Keywords

  • Autophagy
  • Inhibitor
  • Kinase
  • Structure

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