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Updated: Jan 7, 2026
Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System
Published on: December 11, 2016
Drug Development
Brent Clayton1, Steven M Massey2, Shaoyou Chu1
1Indiana University School of Medicine, Indianapolis, IN, USA.
Background:
The role of microglia in neuroinflammation is widely recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Genome-wide association studies have identified PLCγ2 as a key contributor, with specific variants conferring either risk or protection. Notably, the protective PLCγ2•P522R variant is associated with increased mRNA expression, protein levels, and innate activity, whereas the risk variant PLCγ2•M28L shows the opposite trend. Based on these findings, we hypothesize that small molecules capable of enhancing PLCγ2 expression or directly activating the protein could mimic the protective effects of the P522R variant. Such an approach may represent a promising therapeutic strategy to mitigate disease progression and cognitive decline in AD patients.
Method:
We performed high-throughput screening including DNA Encoded Library (DEL) and Affinity Selection Mass Spectrometry (ASMS) using full-length protein to identify novel small molecules which bind to PLCγ2. Target engagement was confirmed using Differential Scanning Fluorimetry (DSF) and Cellular Thermal Shift Assay (CETSA). Structure activity relationship (SAR) studies were performed to synthesize analogs and optimize for binding and cellular pharmacology in IP-One and phagocytosis assays. Top compounds have been studied in vivo to assess pharmacokinetic properties as well as impact on neuroinflammation.
Result:
Novel PLCγ2 activators have been discovered and preliminary optimization has been completed. These compounds have shown positive results for target engagement, biochemical activity, and cellular pharmacology. In silico predictions indicated the molecule structures are suitable CNS drug discovery program starting points.
Conclusion:
Activation of PLCγ2 is a novel therapeutic strategy for treatment of AD. We identified structurally distinct molecular scaffolds capable of enzyme activation and cellular activity. Recommendations for use of probe molecules in target validation studies and the development of lead-like molecules for clinical studies will be made.
Insights
Researchers discovered novel small molecules that activate Phospholipase C gamma 2 (PLCγ2), a key protein in Alzheimer's disease (AD) pathogenesis. This activation may offer a new therapeutic strategy to combat AD progression and cognitive decline.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Microglia-driven neuroinflammation is central to Alzheimer's disease (AD) pathogenesis.
- Genetic studies implicate Phospholipase C gamma 2 (PLCγ2) variants in AD risk and protection.
- Protective PLCγ2 variants correlate with increased protein activity, suggesting therapeutic potential.
Purpose of the Study:
- To identify small molecules that enhance PLCγ2 expression or activity.
- To explore PLCγ2 activation as a therapeutic strategy for AD.
- To mimic the protective effects of the PLCγ2•P522R variant.
Main Methods:
- High-throughput screening (DNA Encoded Library, Affinity Selection Mass Spectrometry) to identify PLCγ2 binders.
- Biochemical and cellular assays (Differential Scanning Fluorimetry, Cellular Thermal Shift Assay, IP-One, phagocytosis) for target engagement and activity.
- Structure-activity relationship studies and in vivo assessments for pharmacokinetics and neuroinflammation impact.
Main Results:
- Discovery of novel small molecule PLCγ2 activators with preliminary optimization.
- Demonstrated target engagement, biochemical efficacy, and cellular pharmacology.
- In silico analysis suggests suitability for central nervous system (CNS) drug discovery.
Conclusions:
- PLCγ2 activation represents a novel therapeutic avenue for Alzheimer's disease.
- Structurally diverse scaffolds capable of enzyme activation and cellular effects were identified.
- Probe molecules are recommended for target validation, with development of lead-like compounds for clinical trials.
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