Targeting STEP in Alzheimer’s Disease via Fragment-Based PROTAC Development

• Applicant: Dr. Julia Schönfeld
• Subject Area: Pharmacy
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573215460

This project aims to develop first-in-class proteolysis-targeting chimeras (PROTACs) for the degradation of Striatal-EnrichedTyrosine Phosphatase (STEP) as a novel therapeutic strategy for Alzheimer’s disease (AD). AD is the most common cause of dementia, affecting over 50 million people globally, primarily those over 65. With an aging population, cases are expected to triple by 2050, highlighting the urgent need for effective treatments. The mechanisms triggering AD remain to be fully elucidated. For decades, research has focused on targeting amyloid-β (Aβ) plaque formation, a hallmark pathological feature of the disease. However, these efforts have largely failed due to adverse effects or limited efficacy. STEP (PTPN5) is a neuron-specific protein tyrosine phosphatase mainly localized in memory-associated brain regions. It regulates neuronal plasticity and synaptic function and has been validated as a therapeutic target in several AD mouse models. Thus, modulating STEP activity may represent a promising strategy to support neuronal plasticity and prevent neuronal loss in the early stages of AD. PTPs are challenging therapeutic targets due to the highly conserved nature of the tyrosine phosphatase active site. However, the recent development of ligands binding to less conserved allosteric binding sites has increased the druggability of this target class. Notably, allosteric ligands can serve as starting points for the design of PROTACs, which offer the unique ability to pharmacologically induce degradation of a target protein, thereby mimicking a genetic knockout phenotype. Furthermore, potent and effective PROTACs can be constructed even from moderate-affinity STEP binders, due to their event-driven mechanism of action (MOA). Leveraging the PROTAC approach, we aim to overcome the limitations of current small-molecule STEP inhibitors. First, potent and selective allosteric STEP ligands will be developed from fragment-sized binders identified in a recent high-throughput screen. These optimized ligands will be employed to design and synthesize STEP-targeting PROTACs, which will be evaluated in a comprehensive assay pipeline incorporating appropriate controls to assess efficacy, specificity, and MOA. The most promising candidates will then be tested in vitro for absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties, with suitable compounds advancing to future in vivo mouse studies. Our overarching goal is to establish proof-of-concept for STEP degradation as a novel AD therapeutic strategy that targets underlying neuronal signaling defects and provides more effective treatment options.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Lutz Tautz