PTP1B inhibitors(Jiangxi University of Traditional Chinese Medicine)

Protein tyrosine phosphatase 1B (PTP1B) is a well-established target for diabetes and obesity due to its involvement in the negative regulation of insulin signaling. It exerts this effect by dephosphorylating the insulin receptor (IR) and insulin receptor substrate (IRS), attenuating insulin activity. It is a protein tyrosine phosphatase (PTP) superfamily member, which includes a wide range of enzymes encoded by 107 distinct genes. The catalytic site of the PTP superfamily is positively charged and highly conserved among its members, which presents a significant challenge to developing inhibitors in terms of selectivity and oral bioavailability. T-cell protein tyrosine phosphatase (TCPTP), which plays a crucial role in the proliferation of T-cells and B-cells, is a close homologue of PTP1B, sharing 74 % sequence similarity within the catalytic domain. Although considerable efforts have been made to develop a selective and potent PTP1B inhibitor, no molecule has yet been developed as a drug. However, a few candidate compounds reached phase II clinical trials, but their further study was discontinued due to suboptimal efficacy and the manifestation of undesirable side effects. In this review, we aimed to decipher the complications associated with the PTP1B enzyme and the design strategies used by various research groups to develop small-molecule inhibitors, emphasising the structure-activity relationship of small molecules synthesized for this target. This review also delineates the molecular features, which will aid in designing rational approaches and foster further research into this target of type 2 diabetes mellitus.