Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction

0569689 - ÚOCHB 2024 RIV US eng J - Článek v odborném periodiku
Nuta, G. C. - Gilad, Y. - Goldberg, N. - Meril, S. - Bahlsen, M. - Carvalho, S. - Kozer, N. - Barr, H. - Sirkis, Y. F. - Hercík, Kamil - Břehová, Petra - Nencka, Radim - Bialik, S. - Eisenstein, M. - Kimchi, A.
Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction.
Autophagy. Roč. 19, č. 8 (2023), s. 2372-2385. ISSN 1554-8627. E-ISSN 1554-8635
Institucionální podpora: RVO:61388963
Klíčová slova: autophagy inhibition * cancer * drug screen * LC3B * pancreatic cancer * protein-fragment complementation assay * small molecules
Obor OECD: Organic chemistry
Impakt faktor: 13.3, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1080/15548627.2023.2178159

Macroautophagy/autophagy is a catabolic process by which cytosolic content is engulfed, degraded and recycled. It has been implicated as a critical pathway in advanced stages of cancer, as it maintains tumor cell homeostasis and continuous growth by nourishing hypoxic or nutrient-starved tumors. Autophagy also supports alternative cellular trafficking pathways, providing a mechanism of non-canonical secretion of inflammatory cytokines. This opens a significant therapeutic opportunity for using autophagy inhibitors in cancer and acute inflammatory responses. Here we developed a high throughput compound screen to identify inhibitors of protein-protein interaction (PPI) in autophagy, based on the protein-fragment complementation assay (PCA). We chose to target the ATG12-ATG3 PPI, as this interaction is indispensable for autophagosome formation, and the analyzed structure of the interaction interface predicts that it may be amenable to inhibition by small molecules. We screened 41,161 compounds yielding 17 compounds that effectively inhibit the ATG12-ATG3 interaction in the PCA platform, and which were subsequently filtered by their ability to inhibit autophagosome formation in viable cells. We describe a lead compound (#189) that inhibited GFP-fused MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) puncta formation in cells with IC50 value corresponding to 9.3 μM. This compound displayed a selective inhibitory effect on the growth of autophagy addicted tumor cells and inhibited secretion of IL1B/IL-1β (interleukin 1 beta) by macrophage-like cells. Compound 189 has the potential to be developed into a therapeutic drug and its discovery documents the power of targeting PPIs for acquiring specific and selective compound inhibitors of autophagy.
Trvalý link: https://hdl.handle.net/11104/0341063