Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.

靶向蛋白质降解是指利用小分子诱导蛋白质的选择性降解。在最常见的形式中，这种降解是通过泛素 E3 连接酶（细胞的主要废物处理机器）与感兴趣的蛋白质靶标之间配体介导的新相互作用来实现，从而导致泛素化和随后的蛋白酶体降解。对偶然发现的降解剂的生物学和机械学理解已经取得了显着的进展。这种更好的理解和新颖的化学不仅为靶向蛋白质降解提供了概念的临床证明，而且还导致了该领域的快速发展，有数十种研究药物处于活跃的临床试验中。两类不同的蛋白质降解疗法正在被广泛探索：双功能 PROTAC 和分子胶降解剂，两者都有其独特的优势和挑战。在这里，我们回顾了靶向蛋白质降解方法的现状以及它们在生物过程中的相似之处。我们还概述了新型降解剂正在进行的临床探索，并就该领域可能采取的方向提供了一些观点。