The Identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets

Maria Zachari, Julie Marie Rainard, George Cherian Pandarakalam, Lindsay Robinson, Jonathan Gillespie, Muralikrishnan Rajamanickam, Veronique Hamon, Angus Morrison, Ian G. Ganley, Stuart Patrick McElroy (Lead / Corresponding author)

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Abstract

Autophagy is a critical cellular homeostatic mechanism, the dysfunction of which has been linked to a wide variety of disease states. It is regulated through the activity of specific kinases, in particular Unc-51 like autophagy activating kinase 1 (ULK1) and Phosphatidylinositol 3-kinase vacuolar protein sorting 34 (VPS34), which have both been suggested as potential targets for drug development. To identify new chemical compounds that might provide useful chemical tools or act as starting points for drug development, we screened each protein against the Published Kinase Inhibitor Set (PKIS), a library of known kinase inhibitors. In vitro screening and analysis of the published selectivity profiles of the hits informed the selection of three relatively potent ATP-competitive inhibitors against each target that presented the least number of off-target kinases in common. Cellular assays confirmed potent inhibition of autophagy in response to two of the ULK1 inhibitors and all three of the VPS34 inhibitors. These compounds represent not only a new resource for the study of autophagy but also potential chemical starting points for the validation or invalidation of these two centrally important autophagy kinases in disease models.

Original languageEnglish
Pages (from-to)801-814
Number of pages14
JournalBiochemical Journal
Volume477
Issue number4
Early online date3 Feb 2020
DOIs
Publication statusPublished - 27 Feb 2020

Keywords

  • autophagy
  • chemical biology
  • high-throughput screening
  • kinases

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    Zachari, M., Rainard, J. M., Pandarakalam, G. C., Robinson, L., Gillespie, J., Rajamanickam, M., Hamon, V., Morrison, A., Ganley, I. G., & McElroy, S. P. (2020). The Identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets. Biochemical Journal, 477(4), 801-814. https://doi.org/10.1042/BCJ20190846