Exploring Ligand-Directed N-Acyl-N-alkylsulfonamide-Based Acylation Chemistry for Potential Targeted Degrader Development,ACS Medicinal Chemistry Letters

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Exploring Ligand-Directed N-Acyl-N-alkylsulfonamide-Based Acylation Chemistry for Potential Targeted Degrader Development
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-07-21 , DOI: 10.1021/acsmedchemlett.1c00285
Mingxing Teng _{1,

2} , Jie Jiang _{1,

2} , Scott B Ficarro _{1,

3,

4} , Hyuk-Soo Seo _{1,

2} , Jae Hyun Bae ₁ , Katherine A Donovan _{1,

2} , Eric S Fischer _{1,

2} , Tinghu Zhang ₅ , Sirano Dhe-Paganon _{1,

2} , Jarrod A Marto _{1,

3,

4} , Nathanael S Gray ₅

Affiliation

Ligand-directed bioconjugation strategies have been used for selective protein labeling in live cells or tissue samples in applications such as live-cell imaging. Here we hypothesized that a similar strategy could be used for targeted protein degradation. To test this possibility, we developed a series of CDK2-targeting N-acyl-N-alkylsulfonamide (NASA)-containing acylation probes. The probes featured three components: a CDK2 homing ligand, a CRL4^CRBN E3 ligase recruiting ligand, and a NASA functionality. We determined that upon target binding, NASA-mediated reaction resulted in selective functionalization of Lys89 on purified or native CDK2. However, we were unable to observe CDK2 degradation, which is in contrast to the efficient degradation achieved by the use of a structurally similar reversible bivalent degrader. Our analysis suggests that the lack of degradation is due to the failure to form a productive CDK2:CRBN complex. Therefore, although this work demonstrates that NASA chemistry can be used for protein labeling, whether this strategy could enable efficient protein degradation remains an open question.

中文翻译：

探索基于配体导向的 N-酰基-N-烷基磺酰胺的酰化化学，以开发潜在的靶向降解剂

在活细胞成像等应用中，以配体为导向的生物偶联策略已被用于在活细胞或组织样本中进行选择性蛋白质标记。在这里，我们假设类似的策略可用于靶向蛋白质降解。为了测试这种可能性，我们开发了一系列以 CDK2 为目标的N-酰基-N-烷基磺酰胺 (NASA) 酰化探针。探针具有三个组成部分：CDK2 归巢配体、CRL4 ^CRBNE3 连接酶招募配体，以及 NASA 功能。我们确定，在目标结合后，NASA 介导的反应导致 Lys89 在纯化或天然 CDK2 上的选择性功能化。然而，我们无法观察到 CDK2 的降解，这与使用结构相似的可逆二价降解剂实现的有效降解形成对比。我们的分析表明，缺乏降解是由于未能形成高效的 CDK2:CRBN 复合物。因此，尽管这项工作表明 NASA 化学可以用于蛋白质标记，但这种策略是否可以实现有效的蛋白质降解仍然是一个悬而未决的问题。

更新日期：2021-08-12

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