Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00569689" target="_blank" >RIV/61388963:_____/23:00569689 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1080/15548627.2023.2178159" target="_blank" >https://doi.org/10.1080/15548627.2023.2178159</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1080/15548627.2023.2178159" target="_blank" >10.1080/15548627.2023.2178159</a>
Alternative languages
Result language
angličtina
Original language name
Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Autophagy
ISSN
1554-8627
e-ISSN
1554-8635
Volume of the periodical
19
Issue of the periodical within the volume
8
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
2372-2385
UT code for WoS article
000935235000001
EID of the result in the Scopus database
2-s2.0-85148615503