This study identifies an unusual sulfur-based chemical as a novel and specific inhibitor of the tyrosine phosphatase STEP and shows that it can improve the cognitive function of a mouse model of Alzheimer's disease.

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

The development of low μM inhibitors of the Mycobacterium tuberculosis phosphatase PtpA is reported. The most potent of these inhibitors (K i = 1.4 ± 0.3 μM) was found to be selective when tested against a panel of human tyrosine and dual-specificity phosphatases (11-fold vs the highly homologous HCPtpA, and >70-fold vs all others tested). Modeling the inhibitor-PtpA complexes explained the structure-activity relationships observed in vitro and revealed further possibilities for compound development. KeywordsMycobacterium tuberculosis; Phosphatase; Inhibitor; PtpA Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Out of over 13 million active cases each year, TB causes nearly 2 million deaths. 1 Current treatment of drug-sensitive strains requires 6-9 months to fully eradicate the infection. New Mtb drugs that act on novel targets are needed to shorten treatment and address the emergence of antibiotic resistance.Mtb encodes two protein tyrosine phosphatases (PTPs), PtpA and PtpB, that are promising new targets for TB drug development. 2 These PTPs are secreted by Mtb 3 into the cytosol of infected macrophages, obviating the need for inhibitors to enter bacterial cells. 4 Although genetic deletion of PtpA or PtpB does not affect Mtb growth in culture, 4,5 these deletions severely attenuate growth in sensitive infected macrophages. 4 These data suggest that the Mtb PTPs act on macrophage signaling pathways to promote Mtb survival in the infected host. Although not classical drug targets because they are not essential in vitro, targeting the secreted PTPs in the host macrophage circumvents two central resistance mechanisms of Mtb; that is, poor drug permeability due to the Mtb cell wall, 6 and pump-mediated drug efflux. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe previously reported the development of low-molecular weight inhibitors of PtpB 8 using a substrate-based, fragment identification and optimization approach termed Substrate Activity Screening (SAS). 9 Here, we applied the same method to PtpA to prepare and evaluate a library of inhibitors selective for Mtb PtpA. These studies identified low-micromolar PtpA inhibitors with selectivity versus a panel of human phosphatases. Modeling our compounds bound in the active site of PtpA explained the observed structure-activity relationships (SAR) and highlighted further possibilities for compound development.A library of O-aryl phosphate substrate fragments was previously developed to target PtpB. 8 Using this library, we identified compounds for further optimization towards PtpA. Due to the ease of synthetic diversification of aryl difluoromethylphosphonic acid (DFMP) inhibitors, we varied DFMP analogs to establish SAR for PtpA inhibition. Although DFMP inhibitors have traditionally exhibited poor cell permeability due to the dianionic nature of this pharmacophore, DFMP inhibitors of the human phosphatase PTP1B, an enzyme involved in insulin signaling, have rece...