Small molecule inhibitors of proteins represent important medicines and critical chemical tools to investigate the biology of the target proteins. Advances in various -omics technologies have fueled the pace of discovery of disease-relevant proteins. Translating these discoveries into human benefits requires us to develop specific chemicals to inhibit the proteins. However, traditional small molecule inhibitors binding to orthosteric or allosteric sites face significant challenges. These challenges include drug selectivity, therapy resistance as well as drugging undruggable proteins and multi-domain proteins. To address these challenges, PROteolysis TArgeting Chimera (PROTAC) has been proposed. PROTACs are heterobifunctional molecules containing a binding ligand for a protein of interest and E3 ligase-recruiting ligand that are connected through a chemical linker. Binding of a PROTAC to its target protein will bring a E3 ligase in close proximity to initiate polyubiquitination of the target protein ensuing its proteasome-mediated degradation. Unlike small molecule inhibitors, PROTACs achieve target protein degradation in its entirety in a catalytical fashion. In this review, we analyze recent advances in PROTAC design to discuss how PROTACs can address the challenges facing small molecule inhibitors to potentially deliver next-generation medicines and chemical tools with high selectivity and efficacy. We also offer our perspectives on the future promise and potential limitations facing PROTACs. Investigations to overcome these limitations of PROTACs will further enhance the promise of PROTACs for human benefits.

蛋白质的小分子抑制剂是研究目标蛋白质生物学的重要药物和关键化学工具。各种组学技术的进步推动了发现疾病相关蛋白的步伐。将这些发现转化为人类利益需要我们开发特定的化学物质来抑制蛋白质。然而，与正构或变构位点结合的传统小分子抑制剂面临重大挑战。这些挑战包括药物选择性、治疗抗性以及药物不可成药的蛋白质和多域蛋白质。为了应对这些挑战，提出了蛋白水解靶向嵌合体 (PROTAC)。PROTACs 是异双功能分子，包含目标蛋白质的结合配体和通过化学接头连接的 E3 连接酶募集配体。PROTAC 与其靶蛋白的结合将使 E3 连接酶靠近以启动靶蛋白的多泛素化，从而导致其蛋白酶体介导的降解。与小分子抑制剂不同，PROTACs 以催化方式完全降解靶蛋白。在这篇综述中，我们分析了 PROTAC 设计的最新进展，以讨论 PROTAC 如何应对小分子抑制剂面临的挑战，以潜在地提供具有高选择性和功效的下一代药物和化学工具。我们还就 PROTAC 面临的未来承诺和潜在限制提供了我们的观点。