A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions.
A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions.
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在微型条件下，靶向嵌合体（快速）的蛋白水解快速合成的平台。
DOI：
10.1016/j.ejmech.2022.114317
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发表时间：
2022-06-05
影响因子：
6.7
通讯作者：
Tang, Weiping
中科院分区：
文献类型：
--
作者：
Guo, Le;Zhou, Yaxian;Nie, Xueqing;Zhang, Zhongrui;Zhang, Zhen;Li, Chunrong;Wang, Taobo;Tang, Weiping
靶向嵌合体（Protac）是靶向蛋白质降解的最常用技术之一。 Protac由靶蛋白配体，E3连接酶配体及其之间的连接器组成。开发Protac的传统方法涉及逐步合成，并且很耗时。本文中，我们报告了一个通过在靶向蛋白质的配体上的邻苯二甲醛（OPA）基序之间的无可碰撞偶联反应快速合成Protac（Rapid-TAC）的平台。由不同的E3连接酶配体以及连接器的各种类型和长度组成。在我们优化的小型化条件下，可以以高通量方式合成完整的Protac，并且可以将产品直接用于筛选，而无需任何进一步的操作（包括纯化）。我们通过Quikcly识别为雄激素受体（AR）和BRD4分别以41.9 nm和8.9 nm的DC50来证明了该平台的实用性。可以预期，这个快速TAC平台可以很容易地扩展到许多其他目标，从而降低了该新型模型的障碍，以进行小分子药物发现并促进结构活动关系研究。
水作为唯一的副产品；没有纯化并在细胞测定中进行测试
报道了快速合成Protac（Rapid-TAC）的平台。在小型条件下，邻苯二甲醛和胺之间的反应是DMSO中迅速生成Protac库的关键。这些产品可用于筛查，而无需任何Purificaiton。快速识别针对AR和BRD4的主动Protac证明了快速-TAC平台的效用
Proteolysis targeting chimera (PROTAC) is one of the most frequently used technologies for targeted protein degradation. PROTACs are composed of target protein ligand, E3 ligase ligand and a linker between them. Traditional methods for the development of PROTACs involve step-by-step synthesis and are time consuming. Herein, we report a platform for the rapid synthesis of PROTACs (Rapid-TAC) via a traceless coupling reaction between ortho-phthalaldehyde (OPA) motif on the ligand of targeting protein and an amine fucntional group on the commercially available partial PROTAC library that is composed of different E3 ligase ligands and various types and lengths of linkers. Under our optimized miniaturized conditions, the full PROTACs can be synthesized in a high throughput manner and the products can be directly used for screening without any further manipulations including purification. We demonstrated the utility of this platform by quikcly identifing active degraders for androgen receptor (AR) and BRD4 with DC50 of 41.9 nM and 8.9 nM, respectively. It is expected that this Rapid-TAC platform can be easily extended to many other targets, thus lowering the barrier to access this novel modelity for small molecule drug discovery and faciliate structure activity relationship studies. Water as the only byproduct; Without purification and tested in cell assay A platform for the rapid synthesis of PROTACs (Rapid-TAC) is reported. The reaction between ortho-phthalaldehyde and amine is the key for the quick generation of a library of PROTACs in DMSO under miniaturized conditions. The products can be used for screening without any purificaiton. The utility of the Rapid-TAC platform is demonstrated by the quick identification of active PROTACs against AR and BRD4
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影响因子：
7.3
作者：
Han X;Zhao L;Xiang W;Qin C;Miao B;McEachern D;Wang Y;Metwally H;Wang L;Matvekas A;Wen B;Sun D;Wang S
通讯作者：
Wang S
影响因子：
16.6
作者：
Buckley, Dennis L.;Crews, Craig M.
通讯作者：
Crews, Craig M.
影响因子：
7.3
作者：
Guo, Chuangxing;Linton, Angelica;Fanjul, Andrea N.
通讯作者：
Fanjul, Andrea N.
影响因子：
5.2
作者：
Qiu, Xing;Sun, Ning;Jiang, Biao
通讯作者：
Jiang, Biao
影响因子：
7.3
作者：
Wurz, Ryan P.;Dellamaggiore, Ken;Ceet, Victor J.
通讯作者：
Ceet, Victor J.