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.