The striatal-enriched protein tyrosine phosphatase (STEP) is a neuron-specific enzyme whose overactivity has been implicated in several neurological disorders, such as Alzheimer's disease, schizophrenia, and fragile X syndrome. Through dephosphorylation of downstream proteins ERK1/2, p38, Fyn, Pyk2, the N-methyl-D-aspartate receptor (NMDAR), and the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), STEP interferes with synaptic function, contributing to cognitive deficits. Recent studies have demonstrated that STEP knockdown in Alzheimer's disease mouse models results in a restoration of cognitive function. Thus STEP has been validated as a potential therapeutic target. To date, the inhibition of phosphatases using a series of reactive warheads which attack the enzymes's active sites have proven relatively unsuccessful. The present proposal describes research plans for the development and study of reversible covalent inhibitors of STEP's activity, which take advantage of the PTP's oxidative sensitivity. In parallel, two promising classes of compounds will be examined: benzopentathiepins and seleninic acids. Structurally and electronically diverse members of the two inhibitor families will be synthesized and screened for STEP inhibition. Compound variation will be geared towards elucidating the specific molecular determinants of the interactions between protein and inhibitor. The biological mechanism of action for these small molecules will be studied in detail through the use of protein pull-down assays, isolation of STEP*inhibitor adducts, and subsequent spectroscopic studies. Furthermore, a thorough analysis of the process by which the cellular reductant glutathione diminishes the potency of these inhibitors will be undertaken. Molecular biology tools, mechanistic exploration, and traditional medicinal chemistry protocols will be combined in the simultaneous investigation of two distinct classes of mechanism-based inhibitors. This work could ultimately be applied to the study of Alzheimer's disease and inspire efforts to target and treat other phosphatase-related disorders.
Increased levels of the striatal-enriched protein tyrosine phosphatase (STEP) have been observed in several neurological disorders, including Alzheimer's disease, in which its heightened activity results in cognitive dysfunction. The proposed research strategy involves the development and investigation of potent and selective inhibitors of STEP using an innovative oxidation-based approach. These studies should lead to new probes for understanding STEP's role in Alzheimer's disease and inspire future endeavors for targeting and treating phosphatase-related disorders.
| Halskov, Kim Søholm; Witten, Michael R; Hoang, Gia L et al. (2018) Rhodium(III)-Catalyzed Imidoyl C-H Activation for Annulations to Azolopyrimidines. Org Lett 20:2464-2467 |
| Witten, Michael R; Wissler, Lisa; Snow, Melanie et al. (2017) X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. J Med Chem 60:9299-9319 |
