Fluorescent probes and degraders of the sterol transport protein Aster-A,Bioorganic & Medicinal Chemistry

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Fluorescent probes and degraders of the sterol transport protein Aster-A
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2024-03-02 , DOI: 10.1016/j.bmc.2024.117673
Nianzhe He ₁ , Laura Depta ₁ , Sonja Sievers ₂ , Luca Laraia ₁

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Our understanding of sterol transport proteins (STPs) has increased exponentially in the last decades with advances in the cellular and structural biology of these important proteins. However, small molecule probes have only recently been developed for a few selected STPs. Here we describe the synthesis and evaluation of potential proteolysis-targeting chimeras (PROTACs) based on inhibitors of the STP Aster-A. Based on the reported Aster-A inhibitor autogramin-2, ten PROTACs were synthesized. Pomalidomide-based PROTACs functioned as fluorescent probes due to the intrinsic fluorescent properties of the aminophthalimide core, which in some cases was significantly enhanced upon Aster-A binding. Most PROTACs maintained excellent binary affinity to Aster-A, and one compound, , showed promising Aster-A degradation in cells. The tools developed here lay the foundation for optimizing Aster-A fluorescent probes and degraders and studying its activity and function in vitro and in cells.

中文翻译：

甾醇转运蛋白 Aster-A 的荧光探针和降解剂

过去几十年来，随着这些重要蛋白质的细胞和结构生物学的进步，我们对甾醇转运蛋白 (STP) 的了解呈指数级增长。然而，最近才针对少数选定的 STP 开发了小分子探针。在这里，我们描述了基于 STP Aster-A 抑制剂的潜在蛋白水解靶向嵌合体 (PROTAC) 的合成和评估。基于已报道的 Aster-A 抑制剂 autogramin-2，合成了 10 种 PROTAC。基于泊马度胺的 PROTAC 由于氨基邻苯二甲酰亚胺核心的固有荧光特性而充当荧光探针，在某些情况下，在 Aster-A 结合后荧光特性显着增强。大多数 PROTAC 与 Aster-A 保持优异的二元亲和力，并且一种化合物，在细胞中显示出有希望的 Aster-A 降解作用。这里开发的工具为优化 Aster-A 荧光探针和降解剂以及研究其体外和细胞内活性和功能奠定了基础。

更新日期：2024-03-02

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