Krishnan, N., Konidaris, K. F., Gasser, G., Tonks, N. K. (February 2018) A potent, selective and orally bioavailable inhibitor of the protein tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models. J Biol Chem, 293 (5). pp. 1517-1525. ISSN 0021-9258
Abstract
The protein tyrosine phosphatase PTP1B is a negative regulator of insulin and leptin signaling, and a highly validated therapeutic target for diabetes and obesity. Conventional approaches to drug development have produced potent and specific PTP1B inhibitors, but these inhibitors lack oral bioavailability, which limits their potential for drug development. Here we report that DPM-1001, an analogue of the specific PTP1B inhibitor trodusquemine (MSI-1436), is a potent, specific and orally bioavailable inhibitor of PTP1B. DPM-1001 also chelates copper, which enhanced its potency as a PTP1B inhibitor. DPM-1001 displayed anti-diabetic properties that were associated with enhanced signaling through insulin and leptin receptors in animal models of diet-induced obesity. Therefore, DPM-1001 represents a proof of concept for a new approach to therapeutic intervention in diabetes and obesity. Although the PTPs have been considered undruggable, the findings of this study suggest that allosteric PTP inhibitors may help reinvigorate drug development efforts that focus on this important family of signal transducing enzymes.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Drug Discovery Type 2 diabetes obesity phosphorylation signal transduction tyrosine-protein phosphatase (tyrosine phosphatase) |
| Subjects: | diseases & disorders > nutritional and metabolic diseases > diabetes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Signal Transduction CSHL labs > Tonks lab Northwell Health CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 2 February 2018 |
| Date Deposited: | 14 Dec 2017 16:10 |
| Last Modified: | 26 Oct 2020 16:11 |
| PMCID: | PMC5798283 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35726 |
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