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
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DOI：
10.1021/jacs.1c05269
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发表时间：
2021-07-08
影响因子：
15
通讯作者：
Staben, Steven T.
中科院分区：
文献类型：
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作者：
den Besten, Willem;Verma, Kshitij;Staben, Steven T.
我们推测，E3相互作用小分子的邻位驱动泛素化可能影响E3泛素连接酶的降解。对一系列与XIAP BIR2结构域结合的小分子进行了修饰，添加了亲核伯胺。这种修饰将XIAP粘结剂转化为XIAP降解的诱导剂。XIAP的降解是依赖于E1和蛋白酶体的，依赖于XIAP的连接酶功能，并通过微小的小分子修饰来挽救，这将避免泛素化。我们证明了在体外泛素化的小分子依赖于它与XIAP的相互作用。综上所述，这些结果证明了设计的工程小分子泛素化和一种新的方法来降解E3泛素连接酶。
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.