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

Povzetek

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.

Ključne besede

antagonists;degradation;ligands;mixtures;peptides;proteins;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 543.645.6:615.4:54
COBISS: 147303683 Povezava se bo odprla v novem oknu
ISSN: 1520-4804
Št. ogledov: 20
Št. prenosov: 6
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: antagonisti;razgradnja;ligandi;zmesi;proteini;Farmacevtska kemija;Peptidi;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 4703-4733
Letnik: ǂVol. ǂ66
Zvezek: ǂiss. ǂ7
Čas izdaje: 2023
DOI: 10.1021/acs.jmedchem.2c01817
ID: 18937215