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  3. Primary Amine Tethered Small Molecules Promote the Degradation of X-Linked Inhibitor of Apoptosis Protein

Primary Amine Tethered Small Molecules Promote the Degradation of X-Linked Inhibitor of Apoptosis Protein

  • J Am Chem Soc. 2021 Jul 21;143(28):10571-10575. doi: 10.1021/jacs.1c05269.
Willem den Besten,  Kshitij Verma,  Sayumi Yamazoe,  Nicole Blaquiere,  Wilson Phung,  Anita Izrael-Tomasevic,  Melinda M Mulvihill,  Elizabeth Helgason,  Sumit Prakash,  Tatiana Goncharov,  Domagoj Vucic,  Erin Dueber,  Wayne J Fairbrother,  Ingrid Wertz,  Kebing Yu,  Steven T Staben
PMID: 34236858 DOI: 10.1021/jacs.1c05269
Abstract

We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could affect the degradation of E3 ubiquitin ligases. A series of XIAP BIR2 domain-binding small molecules was modified to append a nucleophilic primary amine. This modification transforms XIAP binders into inducers of XIAP degradation. The degradation of XIAP is E1- and proteasome-dependent, dependent on the ligase function of XIAP, and is rescued by subtle modifications of the small molecule that would obviate ubiquitylation. We demonstrate in vitro ubiquitylation of the small molecule that is dependent on its interaction with XIAP. Taken together, these results demonstrate the designed ubiquitylation of an engineered small molecule and a novel approach for the degradation of E3 ubiquitin ligases.

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