20.500.12556/RUL-145892 Heterobifunctional ligase recruiters enable pan-degradation of inhibitor of apoptosis proteins 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. antagonists degradation ligands mixtures peptides proteins pharmaceutical chemistry antagonisti razgradnja ligandi zmesi proteini farmacevtska kemija peptidi true false true Angleški jezik Slovenski jezik Članek v reviji 2023-05-17 11:47:21 2023-05-17 11:47:25 2023-05-18 04:00:39 0000-00-00 00:00:00 2023 0 0 Str. 4703-4733 iss. 7 Vol. 66 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 543.645.6:615.4:54 1520-4804 10.1021/acs.jmedchem.2c01817 147303683 acs.jmedchem.2c01817brezvodnegatiska.pdf acs.jmedchem.2c01817brezvodnegatiska.pdf 1 9B9FC02E128D4D5A26737AE566E28324 a5ec1448480374228cb78302fbbaa01f38cb1d918c95bd6f26dbd0db8cda3d74 6d4f3e2c-f4a4-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=168976 https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01817 1 936ee5af-f497-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=168962 Fakulteta za farmacijo 0 0 0