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Autophagy is responsible for degradation and recycling of damaged cellular contents, as misfolded proteins, aggregates and organelles [1]. Its deregulation is linked to different health disorders and in recent years is under evaluation as a target for cancer treatment. In human cells, autophagy is initiated through ULK1 complex, which triggers the activation of the autophagy cascade upon nutrient starvation or energy stress signals [2, 3].
ULK1 complex is composed of the serine/threonine protein kinase ULK1 (unc-51-like kinase 1), FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG (autophagy-related protein) 13 (ATG13), and ATG101. In addition to stress stimuli, ULK1 activation passes through an autophosphorylation mechanism encompassing Thr180, whose mutation determines a dramatic drop in the activity [4].
Particularly ULK1 represents an intriguing target for autophagy modulation and related disorders restoration; in this perspective a structure-based drug discovery campaign has been initiated.
We succeeded in producing the ULK1 kinase domain and setting up a small molecule autophosphorylation-based screening, which has been implemented, in collaboration with the HTS Core Facility of University of Trento, for the identification of active molecules from two libraries (TimTec and KCGS). Different chemotypes have been identified, endowed with low nanomolar to micromolar activities. Efforts are being attained for the structural basis characterization: an X-ray crystal structure of ULK1-inhibitor complex has been obtained so far, paving the way for a future SAR study.
[1] Lin M. G., Hurley J. H Curr Opin Cell Biol. 2016, 39: 61–68.
[2] Mizushima N., Levine B., Cuervo A. M., and Klionsky D.J. Nature. 2008, February 28; 451(7182): 1069–1075.
[3] Levy J.M.M., Zahedi S., Griesinger A.M., Morin A., Davies K.D., Aisner D.L., Kleinschmidt-DeMasters B.K., Fitzwalter B.E., Goodall M.L., Thorburn J., Amani V., Donson A.M., Birks D., Mirsky D.M., Hankinson T.C., Handler M.H., Green A.L., Vibhakar R., Foreman N.K., Thorburn A. eLife. 2017 January 17; doi.org/10.7554/eLife.19671.001.
[4] Lazarus M. B., Novotny C. J., Shokat K. M. ACS Chem. Biol. 2015, 10, 1, 257–261.
