Synthesis of proteolysis targeting chimeras (PROTACs) involves conjugation of an E3 ligase binding ligand to a ligand targeting a protein of interest via a rigid or flexible chemical linker. The choice of linker conjugation site on these ligands can be informed by structural analysis of ligand-target binding modes, the feasibility of synthetic procedures to access specific sites, and computational modeling of predicted ternary complex formations. Small molecules that target bromodomains - epigenetic readers of lysine acetylation - typically offer several potential options for linker conjugation sites. Here we describe how varying the linker attachment site (exit vector) on a CBP/p300 bromodomain ligand along with linker length affects PROTAC degradation activity and ternary complex formation. Using kinetic live cell assays of endogenous CBP and p300 protein abundance and bead-based proximity assays for ternary complexes, we describe the structure-activity relationships of a diverse library of CBP/p300 degraders (dCBPs).

中文翻译：

---

探索布罗莫结构域配体-接头缀合位点以实现有效的 CBP/p300 异双功能降解剂活性

蛋白水解靶向嵌合体 (PROTAC) 的合成涉及通过刚性或柔性化学接头将 E3 连接酶结合配体与靶向目标蛋白质的配体缀合。这些配体上接头缀合位点的选择可以通过配体-靶标结合模式的结构分析、进入特定位点的合成程序的可行性以及预测的三元复合物形成的计算模型来了解。靶向溴结构域（赖氨酸乙酰化的表观遗传解读器）的小分子通常为接头缀合位点提供几种潜在的选择。在这里，我们描述了改变 CBP/p300 溴结构域配体上的接头附着位点（退出向量）以及接头长度如何影响 PROTAC 降解活性和三元复合物形成。使用内源性 CBP 和 p300 蛋白质丰度的动态活细胞测定以及三元复合物基于珠的邻近测定，我们描述了多种 CBP/p300 降解剂 (dCBP) 文库的结构-活性关系。