7kh8
Human LMPTP in complex with inhibitorHuman LMPTP in complex with inhibitor
Structural highlights
FunctionPPAC_HUMAN Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. Isoform 3 does not possess phosphatase activity. Publication Abstract from PubMedObesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice. Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase.,Stanford SM, Diaz MA, Ardecky RJ, Zou J, Roosild T, Holmes ZJ, Nguyen TP, Hedrick MP, Rodiles S, Guan A, Grotegut S, Santelli E, Chung TDY, Jackson MR, Bottini N, Pinkerton AB J Med Chem. 2021 May 13;64(9):5645-5653. doi: 10.1021/acs.jmedchem.0c02126. Epub , 2021 Apr 29. PMID:33914534[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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