A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models

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 analog 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. 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 analog 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.