# Development of STEP Allosteric Inhibitors as Novel Therapeutics for Alzheimer's Disease

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $902,529

## Abstract

PROJECT SUMMARY
STriatal-Enriched Tyrosine Phosphatase (STEP) is a neuron-specific protein tyrosine phosphatase (PTP) and a
novel therapeutic target for Alzheimer's disease (AD), a debilitating neurodegenerative disorder for which
currently no cure exists. Recent studies indicate that STEP is overactive in AD and other neurodegenerative and
neuropsychiatric disorders. The emergent model suggests that the increase in STEP activity interferes with
synaptic function and contributes to the characteristic cognitive and behavioral deficits in these diseases.
Knockout or pharmacological inhibition of STEP in a mouse model of AD decreases the biochemical and
cognitive deficits in these mice, validating STEP as a novel drug target for the treatment of AD. However, the
only reported STEP inhibitor with cellular and in vivo activity is a benzopentathiepin (TC-2153) that is known to
modify DNA, thus likely causing adverse effects when given chronically. In this proposal we plan to develop the
first selective and drug-like inhibitors of STEP for proof-of-concept (POC) studies in AD mouse models. Previous
efforts to generate more drug-like STEP inhibitors have failed. These prior high-throughput screening (HTS)
efforts utilized simple biochemical screening assays with truncated STEP constructs that only contained the
catalytic domain. Thus, they favored the identification of compounds that target the highly conserved active site
and are not selective for STEP. We have developed a robust HTS platform based on protein thermal shift (PTS)
technology that can detect small molecule binding to full-length STEP in 384-well format. A sequence of
secondary assays to further characterize hits is in place, as well as crucial collaborations, ensuring the greatest
likelihood of success in the search for small molecules that are suitable for POC studies aimed at establishing a
STEP-based treatment strategy in AD. In Aim 1 we will perform HTS for STEP allosteric inhibitors using our PTS-
based screening platform. We will confirm and characterize hit compounds and select the most promising
scaffolds for chemical optimization in Aim 2, where we will improve STEP inhibitor potency, selectivity, and drug-
like properties. In Aim 3, we will evaluate selected inhibitors in cellular models for efficacy and specificity. Our
overall goal is to develop at least one lead series and one back-up series of potent and specific STEP inhibitor
probes that are ready for subsequent testing and optimization for in vivo studies.

## Key facts

- **NIH application ID:** 10260540
- **Project number:** 5R01AG065387-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Lutz Tautz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $902,529
- **Award type:** 5
- **Project period:** 2020-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260540

## Citation

> US National Institutes of Health, RePORTER application 10260540, Development of STEP Allosteric Inhibitors as Novel Therapeutics for Alzheimer's Disease (5R01AG065387-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10260540. Licensed CC0.

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