PTP1B negatively regulates insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) phosphorylation. Mice that lack the PTP1B gene have increased insulin sensitivity with resistance to weight gain on a high-fat diet and are otherwise normal. This unique combination of desired attributes has driven an intense search for PTP1B inhibitors for treatment of both T2D and obesity. The discovery of effective inhibitors of PTP1B has proven challenging, due to both the selectivity requirements over other protein tyrosine phosphatases, particularly T-cell protein tyrosine phosphatase (TC-PTP) with which it shares high sequence homology near the catalytic site, and the need for potent antagonists to incorporate polar phosphate mimics, thus limiting cell penetration. The Abbott team identified a peripheral site in the X-ray crystal structure of a PTP1B-inhibitor complex. It is located near the catalytic site where the substrate phosphotyrosine residues bind and by using an SAR by NMR approach, identified unique binders to each site. They then linked these fragments to obtain the potent inhibitor 15, containing two free carboxylic acid groups.
Was this article helpful?