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

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

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.

• Jezik: Angleški jezik
• Ključne besede: antagonists, degradation, ligands, mixtures, peptides, proteins, pharmaceutical chemistry
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: Str. 4703-4733
• Številčenje: Vol. 66, iss. 7
• PID: 20.500.12556/RUL-145892
• UDK: 543.645.6:615.4:54
• ISSN pri članku: 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01817
• COBISS.SI-ID: 147303683
• Datum objave v RUL: 17.05.2023

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: antagonisti, razgradnja, ligandi, zmesi, proteini, farmacevtska kemija, peptidi