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

Krystof Skach; Jiri Boserle; Petra Břehová; Ema Chaloupecká; Radim Nencka; Krystof Skach; Gal Chaim Nuta; Shani Bialik; Adi Kimchi; Silvia Carvalho; Noga Kozer; Haim Barr

doi:10.1016/j.bmcl.2024.129939

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

Krystof Skach, Jiri Boserle, Petra Břehová, Ema Chaloupecká, Radim Nencka^*, Krystof Skach, Gal Chaim Nuta, Shani Bialik, Adi Kimchi, Silvia Carvalho, Noga Kozer, Haim Barr

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	129939
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	112
Early online date	27 Aug 2024
DOIs	https://doi.org/10.1016/j.bmcl.2024.129939
Publication status	Published - 1 Nov 2024

Funding

The work was supported by the project New Technologies for Translational Research in Pharmaceutical Sciences (NETPHARM, project ID CZ.02.01.01/00/22_008/0004607), co-funded by the European Union. This work was also supported by a Yeda Research and Development Grant and the Czech Academy of Sciences (RVO: 61388963). Publisher Copyright: © 2024 The Author(s)

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2024.129939Licence: CC BY

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Skach, K., Boserle, J., Břehová, P., Chaloupecká, E., Nencka, R., Skach, K., Nuta, G. C., Bialik, S., Kimchi, A., Carvalho, S., Kozer, N., & Barr, H. (2024). Structure–activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein–protein interaction. Bioorganic and Medicinal Chemistry Letters, 112, Article 129939. https://doi.org/10.1016/j.bmcl.2024.129939

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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.",

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AU - Chaloupecká, Ema

AU - Nencka, Radim

AU - Skach, Krystof

AU - Nuta, Gal Chaim

AU - Bialik, Shani

AU - Kimchi, Adi

AU - Carvalho, Silvia

AU - Kozer, Noga

AU - Barr, Haim

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

Abstract

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