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

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 Ki 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 Ki of 110 nM, with 15–60-fold
selectivity across a series of phosphatases.