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@ARTICLE{Ng:274581,
author = {Y. L. D. Ng and A. Bricelj and J. A. Jansen and A.
Murgai$^*$ and K. Peter and K. A. Donovan and M. Gütschow
and J. Krönke$^*$ and C. Steinebach and I. Sosič},
title = {{H}eterobifunctional {L}igase {R}ecruiters {E}nable
pan-{D}egradation of {I}nhibitor of {A}poptosis {P}roteins.},
journal = {Journal of medicinal chemistry},
volume = {66},
number = {7},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {DKFZ-2023-00658},
pages = {4703-4733},
year = {2023},
note = {2023 Apr 13;66(7):4703-4733},
abstract = {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.},
cin = {BE01},
ddc = {610},
cid = {I:(DE-He78)BE01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36996313},
doi = {10.1021/acs.jmedchem.2c01817},
url = {https://inrepo02.dkfz.de/record/274581},
}