Heterobifunctional ligase recruiters enable pan-degradation of inhibitor of apoptosis proteins

Ng, Yuen Lam Dora (author), Bricelj, Aleša (author), Jansen, Jacqueline A. (author), Murgai, Arunima (author), Peter, Kirsten (author), Donovan, Katherine A. (author), Gütschow, Michael (author), Krönke, Jan (author), Steinebach, Christian (author), Sosič, Izidor (author)

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.

• Language: English
• Keywords: antagonists, degradation, ligands, mixtures, peptides, proteins, pharmaceutical chemistry
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 4703-4733
• Numbering: Vol. 66, iss. 7
• PID: 20.500.12556/RUL-145892
• UDC: 543.645.6:615.4:54
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01817
• COBISS.SI-ID: 147303683
• Publication date in RUL: 17.05.2023

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: antagonisti, razgradnja, ligandi, zmesi, proteini, farmacevtska kemija, peptidi