Jiaqian Wu

Sanford Burnham Prebys Medical Discovery, USA

Title: Discovery and Characterization of Small Molecule Modulators of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) for Alzheimer’s Disease Therapeutics

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Biography

Jiaqian Wu is a Ph.D. candidate at Sanford Burnham Prebys Medical Discovery Institute, specializing in cancer and molecular biology with a focus on fragment-based drug discovery. Her research centers on targeting challenging phosphatases such as STEP and VHR, using high-throughput screening and biophysical techniques to identify novel small molecule modulators and degraders. She has developed and validated first-in-class STEP PROTACs for Alzheimer’s disease, demonstrating in vivo efficacy and blood-brain barrier penetration. She brings expertise in assay development, protein biochemistry, structural biology, and analytical chemistry. Before her Ph.D., she earned her M.S. in Chemistry from UC San Diego, where she studied membrane protein structure using NMR. Her collaborative work has contributed to multiple publications and conference presentations in the fields of neurodegeneration and oncology. She has received several research awards and scholarships and is passionate about translating mechanistic insights into therapeutic innovation.

Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta (A?) peptide and progressive cognitive decline. While therapies targeting A? production, such as ?-secretase inhibitors, have shown limited success, alternative strategies that target early synaptic dysfunction are gaining attention. Striatal-enriched protein tyrosine phosphatase (STEP), a key negative regulator of synaptic strengthening, is aberrantly elevated in AD and contributes to synaptic and cognitive deficits. Importantly, reducing STEP activity genetically or pharmacologically has been shown to reverse these impairments in AD models, validating STEP as a promising therapeutic target.

In this study, we employed a fragment-based drug discovery approach to identify novel STEP-binding molecules. A library of 1,000 fluorinated fragments was screened using ^19F nuclear magnetic resonance (NMR) spectroscopy. Promising hits were further validated using multiple orthogonal biophysical assays, including 1D WaterLOGSY NMR, microscale thermophoresis (MST), and isothermal titration calorimetry (ITC). Based on the most potent and selective fragment, we rationally designed and synthesized a series of proteolysis-targeting chimeras (PROTACs) to induce STEP degradation.

Five candidate STEP PROTACs were characterized in SH-SY5Y neuroblastoma cells, demonstrating effective and selective degradation of STEP. Notably, one compound exhibited blood-brain barrier permeability and achieved potent in vivo STEP degradation.

Our work establishes a novel platform for the discovery of STEP degraders, representing the first-in-class STEP-targeted PROTACs. By addressing upstream synaptic dysfunction rather than downstream A? accumulation, this strategy holds significant promise for developing disease-modifying therapies for AD.