Poster Presentation Inaugural Australian Ubiquitin Summit 2025

A structural, biophysical and cellular toolkit to harness Inhibitor of Apoptosis Proteins (IAPs) for Targeted Protein Degradation (#112)

Nishma Gupta 1 2 , Nicole Trainor 1 2 , Mona Radwan 1 2 3 , Stephanie Nguyen 1 2 , Luke Duncan 1 2 , Andrew X Tang 1 2 , Julia Beveridge 1 2 4 , Noémie Aubourg 1 2 , Natasha Silke 1 2 , Ceren Bilgilier 5 , Johannes Wachter 5 , Peter Greb 5 , Zuzana Jandova 5 , Ján Eliaš 5 , Sara Kopf 5 , Thomas Gerstberger 5 , Peggy Stolt-Bergner 6 , Nina Braun 5 , Harald Weinstabl 5 , Darryl B McConnell 5 7 , Federico Mauri 5 , Isabelle S Lucet 1 2 , John Silke 1 2 , Nicola EA Chessum 5 , Michael J Roy 1 2 8
  1. Walter & Eliza Hall Institute , Parkville, VIC, Australia
  2. Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. Centre for Genetic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, KSA
  4. BioCurate Pty Ltd, Carlton, VIC, Australia
  5. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
  6. Boehringer Ingelheim RCV GmbH & Co KG, Biberach, Germany
  7. Curie.Bio, Boston, MA, USA
  8. Cancer Resistance Program, South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, SA, Australia

Inhibitor of Apoptosis Proteins (IAPs) are key regulators of cell death, often hijacked by cancer cells to evade apoptosis and promote survival. These proteins — such as XIAP, cIAP1/2 —block caspase activity and modulate NF-κB signaling, enabling tumor growth and resistance to chemotherapy and radiotherapy [1]. Overexpression of IAPs is common in many cancers and correlates with poor prognosis. Their central role in suppressing programmed cell death has made IAPs attractive therapeutic targets for the development of potent small molecule antagonists, also known as SMAC mimetics [1]. In addition, many IAPs also possess RING E3 ubiquitin ligase activity, effecting ubiquitination of cellular proteins for proteasomal degradation or to modulate signalling complexes. The E3 ligase activity of IAPs has been successfully exploited for Targeted Protein Degradation (TPD) applications, including heterobifunctional degraders termed Specific non-genetic IAP-based protein erasers (SNIPERs), or IAP-recruiting Protein Degraders (IPDs) [2-4].

Here we present an IAP-directed small molecule toolkit we have developed, with a focus on harnessing IAP proteins for TPD applications. Our platform includes streamlined structural, biophysical and cellular approaches to assess the IAP recruitment and selectivity, as well as the exploration of tag-based target validation studies strategies based on IAP-recruiting degraders. We hope this work provides a useful resource and valuable learnings for the development of IAP-recruiting degrader and SMAC mimetic therapeutics.

  1. Morrish, E; Brumatti, G; Silke, J. Future Therapeutic Directions for Smac-Mimetics. Cells, 2020, 9(2), 406.
  2. Naito, M; Ohoka, N; Shibata, N. SNIPERs-Hijacking IAP activity to induce protein degradation. Drug Discov. Today Technol. 2019, 31, 35-42.
  3. Schiemer, J. et al. Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat. Chem. Biol. 2020, 17, 152-160.
  4. Miah, AH. et al. Optimization of a Series of RIPK2 PROTACs. J. Med. Chem. (2021). 2021, 64, 17, 12978–13003.