TY  - JOUR
AU  - Ng, Yuen Lam Dora
AU  - Bricelj, Aleša
AU  - Jansen, Jacqueline A
AU  - Murgai, Arunima
AU  - Peter, Kirsten
AU  - Donovan, Katherine A
AU  - Gütschow, Michael
AU  - Krönke, Jan
AU  - Steinebach, Christian
AU  - Sosič, Izidor
TI  - Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins.
JO  - Journal of medicinal chemistry
VL  - 66
IS  - 7
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2023-00658
SP  - 4703-4733
PY  - 2023
N1  - 2023 Apr 13;66(7):4703-4733
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36996313
DO  - DOI:10.1021/acs.jmedchem.2c01817
UR  - https://inrepo02.dkfz.de/record/274581
ER  -