<br>抗体-PROTAC 缀合物可实现 BRD4 的 HER2 依赖性靶向蛋白降解。,ACS Chemical Biology

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抗体-PROTAC 缀合物可实现 BRD4 的 HER2 依赖性靶向蛋白降解。
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-04-27 , DOI: 10.1021/acschembio.0c00285
Marı A Maneiro ₁ , Nafsika Forte ₂ , Maria M Shchepinova ₁ , Cyrille S Kounde ₁ , Vijay Chudasama ₂ , James Richard Baker ₂ , Edward W Tate ₁

Affiliation

利用蛋白水解靶向嵌合体 (PROTAC) 靶向蛋白质降解是当前药物发现中备受关注的领域。然而，尽管 PROTAC 对多种靶标的高效性已经得到证实，但迄今为止报道的大多数降解剂显示出有限的内在组织选择性，并且不区分不同类型的细胞。在这里，我们描述了特定细胞类型中选择性蛋白质降解的策略。我们报告了曲妥珠单抗-PROTAC 缀合物 (Ab-PROTAC 3 ) 的设计和合成，其中 E3 连接酶定向的降解剂活性被抗体接头限制，抗体接头可以在抗体 -PROTAC 内化后水解，释放活性 PROTAC 并诱导催化蛋白降解。我们发现， 3选择性地靶向含溴结构域蛋白 4 (BRD4)，仅在 HER2 阳性乳腺癌细胞系中降解，而不会影响 HER2 阴性细胞。使用活细胞共聚焦显微镜，我们显示了结合物的内化和溶酶体运输，特别是在 HER2 阳性细胞中，导致活性 PROTAC 的释放，其数量足以诱导有效的 BRD4 降解。这些研究证明了组织特异性 BRD4 降解的概念验证，克服了 PROTAC 选择性的局限性，具有应用于新靶点的巨大潜力。

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Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4.

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.

更新日期：2020-06-19

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