Department of Chemistry, UF Scripps Biomedical Research, 120 Scripps Way, Jupiter, FL 33458, USA.
Chembiochem. 2022 Sep 16;23(18):e202200275. doi: 10.1002/cbic.202200275. Epub 2022 Jul 28.
Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker connecting the E3 Ubiquitin Ligase (E3 Ubl) and target protein (TP) ligands, which therefore requires tedious optimization. The creation of "split PROTACs" from E3 Ubl and TP ligands modified with residues suitable for them to couple when simply mixed together would allow various combinations to be assessed in a combinatorial fashion, thus greatly easing the workload relative to a one-by-one synthesis of many different PROTACs (proteolysis targeting chimeras). We explore oxime chemistry here for this purpose. We show that PROTAC assembly occurs efficiently when the components are mixed at a high concentration, then added to cells. However, in situ coupling of the TP and E3 Ubl ligands is inefficient when these units are added to cells at lower concentrations.
蛋白水解靶向嵌合体作为探针分子和药物先导物备受关注。它们的活性对连接 E3 泛素连接酶 (E3 Ubl) 和靶蛋白 (TP) 配体的连接体的长度和性质非常敏感，因此需要进行繁琐的优化。通过用适合于简单混合时偶联的残基修饰 E3 Ubl 和 TP 配体，从 E3 Ubl 和 TP 配体中创建“分裂 PROTACs”，可以以组合方式评估各种组合，从而大大减轻相对于许多不同 PROTACs（蛋白水解靶向嵌合体）的逐个合成的工作量。我们在此目的探索肟化学。我们表明，当成分在高浓度下混合然后添加到细胞中时，PROTAC 组装会有效地发生。然而，当这些单元以较低浓度添加到细胞中时，TP 和 E3 Ubl 配体的原位偶联效率不高。
