Heterobifunctional Ligase Recruiters Enable Pan-Degradation of Inhibitor of Apoptosis Proteins

05 September 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enables 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, degraders 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.


E3 ligases
inhibitor of apoptosis proteins
pan-IAP degraders

Supplementary materials

Pan-Degradation of IAPs Supporting Information
Supplementary Data with Supporting Tables, Schemes and Figure. Detailed chemistry and synthetic procedures are provided in this document as well.


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