IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Isabella A Riha, Miguel A Campos, Xiaokang Jin, Fiona Y Wang, Chenlu Zhang, Sara F Dunne, Benjamin F Cravatt, Xiaoyu Zhang
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引用次数: 0

摘要

传统的小分子药物通常直接针对蛋白质的活性,但当蛋白质缺乏合适的功能位点时,就会出现挑战。另一种方法是靶向蛋白质降解(TPD),它将蛋白质引导到细胞机制中进行蛋白水解降解。最近的研究发现了更多适合 TPD 的 E3 连接酶,扩大了这种方法的潜力。其中,DCAF16 已显示出通过 PROTAC 和分子胶机制促进蛋白质降解的前景。在这项研究中,我们开发了一种均相时间分辨荧光(HTRF)测定法来发现新的 DCAF16 结合体。利用内部亲电子库,我们发现了两种非对映化合物,其中一种能与半胱氨酸 C177-179 上的 DCAF16 结合,另一种则能降低其表达。我们证明,共价结合 DCAF16 的化合物可以转化为能够降解 FKBP12 的 PROTAC。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Exploiting the DCAF16-SPIN4 interaction to identify DCAF16 ligands for PROTAC development.

Traditional small molecule drugs often target protein activity directly, but challenges arise when proteins lack suitable functional sites. An alternative approach is targeted protein degradation (TPD), which directs proteins to cellular machinery for proteolytic degradation. Recent studies have identified additional E3 ligases suitable for TPD, expanding the potential of this approach. Among these, DCAF16 has shown promise in facilitating protein degradation through both PROTAC and molecular glue mechanisms. In this study, we developed a homogeneous time resolved fluorescence (HTRF) assay to discover new DCAF16 binders. Using an in-house electrophile library, we identified two diastereomeric compounds, with one engaging DCAF16 at cysteines C177-179 and another reducing its expression. We demonstrated that the compound covalently engaging DCAF16 can be transformed into a PROTAC capable of degrading FKBP12.

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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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