Unlocking DCAFs To Catalyze Degrader Development: An Arena for Innovative Approaches

Chemically induced proximity-based
targeted protein degradation
(TPD) has become a prominent paradigm in drug discovery. With the
clinical benefit demonstrated by certain small-molecule protein degraders
that target the cullin-RING E3 ubiquitin ligases (CRLs), the field
has proactively strategized to tackle anticipated drug resistance
by harnessing additional E3 ubiquitin ligases to enrich the arsenal
of this therapeutic approach. Here, we endeavor to explore the collaborative
efforts involved in unlocking a broad range of CRL4DCAF for degrader drug development. Throughout the discussion, we also
highlight how both conventional and innovative approaches in drug
discovery can be taken to realize this objective. Moving ahead, we
expect a greater allocation of resources in TPD to pursue these high-hanging
fruits.

基于化学诱导邻近机制的靶向蛋白质降解（targeted protein degradation, TPD）现已成为药物研发领域的重要范式。随着部分靶向cullin-RING E3泛素连接酶（cullin-RING E3 ubiquitin ligases, CRLs）的小分子蛋白质降解剂在临床中展现出治疗获益，该领域已主动布局策略，通过发掘更多类型的E3泛素连接酶来丰富这一治疗手段的储备库，以应对潜在的耐药性问题。本研究旨在探索解锁广谱CRL4DCAF以推进降解剂药物开发的协同路径。在本次论述中，我们还将阐明如何兼顾传统与创新的药物研发路径以达成这一目标。展望未来，我们预计该领域将在靶向蛋白质降解领域投入更多资源，攻坚这些极具价值的研究方向。