Diversified design strategies for small-molecule PROTACs: How do we select?

Although PROTAC technology has revolutionized drug discovery by enabling the degradation of previously undruggable proteins, the clinical translation of traditional PROTACs has been hindered by limitations in E3 ligase availability, suboptimal drug-like properties, and a narrow target scope. In recent years, the emergence of diversified novel PROTAC design strategies, such as chaperone-mediated PROTAC (CHAMP), mini-PROTAC, covalent PROTAC, HyTTD, and pro-PROTAC, has elevated the technology to new heights, accelerating its clinical advancement. However, a critical question remains: How can we select the most appropriate strategy among these options? We summarized and analyzed their strengths and limitations, covering optimization and expansion of E3 ligase-dependent and E3 ligase-independent degrader strategies, undruggable targets degrader strategies, linker optimization and expansion strategies, and pro-PROTAC strategies. Furthermore, we provide guidance on selecting appropriate strategies based on specific target characteristics for designing effective PROTAC, with the aim of facilitating the translation of these innovative approaches toward clinical applications.