Research progress of PTP1B inhibitors and degraders

Protein tyrosine phosphatase 1B (PTP1B), a member of the PTP superfamily, inhibits insulin signaling by dephosphorylating the insulin receptor (IR) and its substrates (IRS), making it an important therapeutic target for diabetes and obesity, with potential applications in treating metabolic syndrome. Furthermore, studies have shown that inhibiting PTP1B may also hold promise in diseases such as Alzheimer's disease and fatty liver disease, and may exert therapeutic effects in cancer by suppressing oncogenic signaling pathways. However, developing inhibitors with selectivity and oral bioavailability remains a major challenge due to the positively charged, highly conserved catalytic site of the PTP superfamily and its strong structural similarity to homologous PTPs. PTP1B degraders represent a novel therapeutic strategy that specifically eliminates intracellular PTP1B protein through targeted degradation mechanisms. This approach aims to overcome the "undruggable" limitations of traditional inhibitors and may offer potential treatment avenues for various PTP1B-related diseases. This review summarizes recently reported PTP1B inhibitors and degraders, including natural products, derivatives of natural products, synthetic small molecules, dual-target inhibitors, as well as advances in PTP1B degraders. It aims to provide a foundation for the rational design and further investigation of PTP1B inhibitors and degraders.