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Heterobifunctional ligase recruiters enable pan-degradation of inhibitor of apoptosis proteins [Elektronski vir]Ng, Yuen Lam Dora ...Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enable the ... transfer of ubiquitin tags onto their target proteins, leading to proteasomal degradation. However, several E3 ligases are validated pharmacological targets themselves, of which inhibitor of apoptosis (IAP) proteins are considered druggable in cancer. Here, we report three series of heterobifunctional PROTACs, which consist of an IAP antagonist linked to either von Hippel-Lindau- or cereblon-recruiting ligands. Hijacking E3 ligases against each other led to potent, rapid, and preferential depletion of cellular IAPs. In addition, these compounds caused complete X-chromosome-linked IAP knockdown, which was rarely observed for monovalent and homobivalent IAP antagonists. In cellular assays, hit degrader 9 outperformed antagonists and showed potent inhibition of cancer cell viability. The hetero-PROTACs disclosed herein are valuable tools to facilitate studies of the biological roles of IAPs and will stimulate further efforts toward E3-targeting therapies.Source: Journal of medicinal chemistry [Elektronski vir]. - ISSN 1520-4804 (Vol. 66, iss. 7, 2023, str. 4703-4733)Type of material - e-article ; adult, seriousPublish date - 2023Language - englishCOBISS.SI-ID - 147303683
Author
Ng, Yuen Lam Dora |
Bricelj, Aleša |
Jansen, Jacqueline A. |
Murgai, Arunima |
Peter, Kirsten |
Donovan, Katherine A. |
Gütschow, Michael |
Krönke, Jan |
Steinebach, Christian |
Sosič, Izidor
Topics
Farmacevtska kemija |
Peptidi |
antagonists |
degradation |
ligands |
mixtures |
peptides |
proteins |
antagonisti |
razgradnja |
ligandi |
zmesi |
proteini
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Author | Ng, Yuen Lam Dora ... |
Title | Heterobifunctional ligase recruiters enable pan-degradation of inhibitor of apoptosis proteins [Elektronski vir] |
Publication date | 2023-04-13 |
COBISS.SI-ID | 147303683 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
---|---|---|---|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2022 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Poljub smrti glavnim dejavnikom apoptoze: razvoj razgrajevalcev proteinov BCL-2 in BAX | J1-2485-2020 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Emmy-Noether Program | Kr-3886/2-1 | ||
DFG | SFB-1074 |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Ng, Yuen Lam Dora | ![]() |
Bricelj, Aleša | 53656 |
Jansen, Jacqueline A. | ![]() |
Murgai, Arunima | ![]() |
Peter, Kirsten | ![]() |
Donovan, Katherine A. | ![]() |
Gütschow, Michael | ![]() |
Krönke, Jan | ![]() |
Steinebach, Christian | ![]() |
Sosič, Izidor | 30816 |
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