Structure–activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein–protein interaction

Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein-protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein-protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

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Publication Details

Journal
Bioorganic & Medicinal Chemistry Letters
Published
2024-08-31
DOI
https://doi.org/10.1016/j.bmcl.2024.129939
Citations
2
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
0.77

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article

Structure–activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein–protein interaction

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2 citations
Bioorganic & Medicinal Chemistry Letters
Autophagy in Disease and Therapy
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article

Structure–activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein–protein interaction

Ema Chaloupecká, Noga Kozer, Radim Nencka, Haim Michael Barr, Petra Břehová, Sílvia Carvalho, Gal Chaim Nuta, Shani Bialik, Adi Kimchi, Jiří Böserle, Kryštof Škach
article en
2 citations

Abstract

Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein-protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein-protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

Bioorganic & Medicinal Chemistry LettersVol. 112
Institute of Organic Chemistry (PL), Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ), Weizmann Institute of Science (IL), University of Chemistry and Technology, Prague (CZ)
European Commission, Weizmann Institute of Science, Akademie Věd České Republiky, Research and Development
Openalex Percentile: Top 26%
Autophagy in Disease and Therapy
0.77
DOIOpen Access PDFOpenAlex
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