Protein degraders targeting JAK/STAT3 signaling pathway are emerging therapeutic modalities for human cancers

JAK/Signal transducer and activator of transcription 3 (STAT3) signaling axis plays an important role in tumor progress. Several JAK/STAT3 inhibitors have entered into clinical trials. However, development of JAK/STAT3 inhibitors faces multiple challenges including low selectivity. Targeted protein degradation (TPD) emerges as a distinct therapeutic modality that holds promise for depleting pathogenic "undruggable" proteins. Proteolysis‑targeting chimera (PROTAC) degraders are a key family of molecules designed to mediate the selective degradation of target proteins. Currently, JAK/STAT3 degraders represent a promising strategy to inhibit JAK/STAT3 signaling. Although there were occasional reports on the development of JAK/STAT3 degraders in recent years, a comprehensive review on the recent progresses of the degraders targeting the whole JAK/STAT3 pathway is missing. Here, we systematically summarized the most recent advances of this field. Specifically, we first introduced the components of JAK/STAT3 pathway and its role in tumorigenesis. We also discussed various aspects of PROTACs including its principle, classification and advantages over small-molecule inhibitor. Then, we focused on the most recent progress of protein degraders targeting JAK/STAT3 pathway, including the degraders of the upstream SHP2, BCR-ABL1 and c-SRC s, JAK degraders, STAT3 degraders (including PROTACs and small-molecule natural products) and the downstream c-Myc degraders, Cyclin D1 degraders, MMP9 degraders, VEGF degraders, and protein degraders of BCL2, BCL-XL and MCL-1. Lastly, we discussed potential opportunities and challenges in the development of JAK/STAT3 degraders. We hope this review will provide theoretical basis for future drug design of novel JAK/STAT3 degraders.