Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
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DOI：
10.1021/acsmedchemlett.0c00265
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发表时间：
2020-09-10
影响因子：
4.2
通讯作者：
Lokey, R. Scott
中科院分区：
文献类型：
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作者：
Klein, Victoria G.;Townsend, Chad E.;Lokey, R. Scott
蛋白水解靶向嵌合体（PROTAC）是催化性异双功能分子，其可以通过将泛素E3连接酶募集至靶标来选择性地降解感兴趣的蛋白质，导致其被蛋白酶体泛素化和降解。大多数降解剂位于与大多数膜渗透性药物相关的化学空间之外。虽然许多PROTAC已被描述为在细胞中具有有效活性，但我们对这些化合物的结构和渗透性之间关系的理解仍然有限。在这里，我们描述了一种无标记的方法，用于评估几种基于VH 032的PROTAC及其组分的渗透性，方法是将平行人工膜渗透性测定（PAMPA）和亲脂性渗透效率（LPE）度量相结合。我们的研究结果表明，这两种无细胞膜渗透性测定的组合提供了新的见解PROTAC结构-渗透性关系，并提供了一个概念框架，用于预测PROTAC的物理化学性质，以更好地告知设计更具渗透性和更有效的降解剂。
Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the proteasome. Most degraders lie outside the chemical space associated with most membrane-permeable drugs. Although many PROTACs have been described with potent activity in cells, our understanding of the relationship between structure and permeability in these compounds remains limited. Here, we describe a label-free method for assessing the permeability of several VH032-based PROTACs and their components by combining a parallel artificial membrane permeability assay (PAMPA) and a lipophilic permeability efficiency (LPE) metric. Our results show that the combination of these two cell-free membrane permeability assays provides new insight into PROTAC structure-permeability relationships and offers a conceptual framework for predicting the physicochemical properties of PROTACs in order to better inform the design of more permeable and more effective degraders.