Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton’s tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.

异双功能嵌合降解剂是一类将靶蛋白募集到 E3 泛素连接酶以驱动化合物依赖性蛋白降解的配体。从最初的化学工具发展而来，蛋白质降解剂代表了一种对药物发现越来越感兴趣的机制。作用机制的关键是在靶标、降解剂和 E3 连接酶之间形成三元复合物，以促进泛素化和随后的降解。然而，对三元复杂结构的了解有限，包括几乎没有关于最广泛采用的 E3 之一的研究，即细胞凋亡抑制剂 1 (cIAP1)。在这项工作中，我们结合生化、生物物理和结构研究来表征降解剂介导的布鲁顿酪氨酸激酶和 cIAP1 三元复合物。