Assessing the Cell Permeability of Bivalent Chemical Degraders Using the Chloroalkane Penetration Assay.,ACS Chemical Biology

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Assessing the Cell Permeability of Bivalent Chemical Degraders Using the Chloroalkane Penetration Assay.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-27 , DOI: 10.1021/acschembio.9b00972
Caroline A Foley ₁ , Frances Potjewyd ₁ , Kelsey N Lamb ₁ , Lindsey I James ₁ , Stephen V Frye ₁

Affiliation

Bivalent chemical degraders provide a catalytic route to selectively degrade disease-associated proteins. By linking target-specific ligands with E3 ubiquitin ligase recruiting ligands, these compounds facilitate targeted protein ubiquitination and degradation by the proteasome. Due to the complexity of this multistep mechanism, the development of effective degrader molecules remains a difficult, lengthy, and unpredictable process. Since degraders are large heterobifunctional molecules, the efficacy of these compounds may be limited by poor cell permeability, and an efficient and reliable method to quantify the cell permeability of these compounds is lacking. Herein, we demonstrate that by the addition of a chloroalkane tag on the BRD4 specific degrader, MZ1, cell permeability can be quantified via the chloroalkane penetration assay. By extending this analysis to individual components of the degrader molecule, we have obtained structure-permeability relationships that will be informative for future degrader development, particularly as degraders move into the clinic as potential therapeutics.

中文翻译：

使用氯烷渗透法评估二价化学降解剂的细胞通透性。

二价化学降解剂提供了选择性降解与疾病相关的蛋白质的催化途径。通过将靶标特异性配体与E3泛素连接酶募集配体连接，这些化合物可促进蛋白酶体靶向蛋白的泛素化和降解。由于这种多步机制的复杂性，有效降解分子的开发仍然是一个困难，漫长且不可预测的过程。由于降解剂是大的异双功能分子，这些化合物的功效可能会因细胞渗透性差而受到限制，并且缺乏一种有效而可靠的方法来量化这些化合物的细胞渗透性。在这里，我们证明了通过在BRD4特异性降解剂MZ1上添加氯代烷标记，可以通过氯代烷渗透测定来定量细胞通透性。

更新日期：2019-12-29

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