The identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets.
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.
['Zachari|Maria|M|', 'Rainard|Julie M|JM|', 'Pandarakalam|George C|GC|', 'Robinson|Lindsay|L|', 'Gillespie|Jonathan|J|', 'Rajamanickam|Muralikrishnan|M|', 'Hamon|Veronique|V|', 'Morrison|Angus|A|', 'Ganley|Ian G|IG|', 'McElroy|Stuart P|SP|']
D001343:Autophagy D000071189:Autophagy-Related Protein-1 Homolog D001859:Bone Neoplasms D058546:Class III Phosphatidylinositol 3-Kinases D055808:Drug Discovery D057166:High-Throughput Screening Assays D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D012516:Osteosarcoma D010766:Phosphorylation D047428:Protein Kinase Inhibitors D017346:Protein Serine-Threonine Kinases D014407:Tumor Cells, Cultured
autophagy kinases chemical biology high-throughput screening