One implicated pathway involves striatal-enriched protein tyrosine phosphatase, or STEP, a neuron-specific enzyme that, among other jobs, regulates the trafficking of synaptic glutamate receptors and the activity of a group of widely active kinases. STEP is overactive in AD, in part because it isn't degraded fast enough, and its overactivity disrupts the post-synaptic events that underlie learning and memory. In animal models of AD, knocking out STEP improves cognition. Thus, STEP inhibition is a potential target for treatment of AD. In this issue of PLOS Biology, Jian Xu, Paul Lombroso, and colleagues report their discovery of a new class of STEP inhibitor—a discovery that involved a small but significant bit of serendipity—and demonstrate its potential in an AD animal model.
The authors began by conducting a high-throughput screen of 150,000 compounds, testing the ability of each to inhibit STEP's phosphatase activity. As is usual in such screens, a number of good candidates emerged. These were winnowed down to eight, chosen for their high activity at low concentration and favorable properties, such as likely ability to cross the blood-brain barrier and absence of known toxic moieties, all important for developing a centrally active drug. Following standard practice, next, they synthesized the molecules from scratch, and here got a surprise—the compounds displayed little STEP inhibitory activity. Some chemical detective work revealed the true inhibitor was elemental sulfur, S8, present as an impurity in the commercially obtained samples used in the screening. This ring compound doesn't make a good drug, so the authors investigated a structurally related compound, benzopentathiepin, containing a ring of six carbons fused to a ring of five sulfurs. A derivative, TC-2153, was known to have low toxicity and was likely to cross the blood-brain barrier, and, they found, was a potent inhibitor of STEP.
To test whether TC-2153 could reverse some of the cognitive effects of STEP overactivity, the authors turned to the “triple transgenic” mouse model, with mutations in three genes known to cause AD: presenilin 1, amyloid precursor protein, and tau. Compared to vehicle, intraperitoneal injection of TC-2153 improved spatial working memory, novel object recognition, and reference memory, all standard tests of cognitive function in AD models. The treatment had no effect on either a-beta, found in amyloid plaques outside of cortical neurons, or phospho-tau, found in neurofibrillary tangles inside them, indicating that the beneficial effect of TC-2153 was not due to alteration of events upstream of STEP overactivity.