X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors.

Autor:	Witten MR; Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States., Wissler L; Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Gothenburg, Sweden., Snow M; Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Macclesfield SK10 4TG, United Kingdom., Geschwindner S; Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Gothenburg, Sweden., Read JA; Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Cambridge CB4 0WG, United Kingdom., Brandon NJ; Neuroscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Cambridge, Massachusetts 02139, United States., Nairn AC; Department of Psychiatry, Yale University , New Haven, Connecticut 06520, United States., Lombroso PJ; Department of Psychiatry, Yale University , New Haven, Connecticut 06520, United States.; Child Study Center, Yale University , New Haven, Connecticut 06520, United States., Käck H; Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Gothenburg, Sweden., Ellman JA; Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Nov 22; Vol. 60 (22), pp. 9299-9319. Date of Electronic Publication: 2017 Nov 08.
DOI:	10.1021/acs.jmedchem.7b01292
Abstrakt:	Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer's treatment. We previously reported a substrate-based approach to the development of low molecular weight STEP inhibitors with K i values as low as 7.8 μM. Herein, we disclose the first X-ray crystal structures of inhibitors bound to STEP and the surprising finding that they occupy noncoincident binding sites. Moreover, we utilize this structural information to optimize the inhibitor structure to achieve a K i of 110 nM, with 15-60-fold selectivity across a series of phosphatases.
Databáze:	MEDLINE
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