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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases
Ashley P Dudey1, Jake M Rigby2, Gregory R Hughes1
1School of Biological Sciences, University of East Anglia, Norwich, UK.
Abstract:
The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.
Insights
Researchers identified novel inhibitors for WWP1 and WWP2, crucial enzymes in cancer. Compound 11, derived from structure-activity relationship studies, shows significant inhibitory potential, offering a promising foundation for developing new cancer therapeutics targeting these E3 ubiquitin ligases.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- HECT E3 ubiquitin ligases WWP1 and WWP2 regulate tumor suppressor protein degradation.
- Dysregulation of WWP1 and WWP2 is implicated in various cancers and diseases.
- Limited availability of specific inhibitors hinders therapeutic development.
Purpose of the Study:
- To identify and develop novel inhibitors targeting WWP1 and WWP2.
- To explore the structure-activity relationship of identified compounds.
- To provide a basis for future lead compound development for cancer therapy.
Main Methods:
- High-throughput screening for initial inhibitor identification (NSC-217913).
- Structure-activity relationship (SAR) studies through chemical synthesis.
- Molecular docking simulations to predict binding interactions.
- Enzyme inhibition assays to determine IC50 values.
Main Results:
- NSC-217913 identified as an initial WWP1 inhibitor (IC50 = 158.3 µM).
- Compound 11 demonstrated enhanced potency against WWP1 (IC50 = 32.7 µM) and WWP2 (IC50 = 269.2 µM).
- Molecular docking revealed favorable interactions of the imidazo[4,5-b]pyrazine scaffold within the enzyme active site.
Conclusions:
- Compound 11 represents a significant advancement in WWP1 and WWP2 inhibitor development.
- The identified scaffold and interactions provide a strong foundation for optimizing future drug candidates.
- Targeting WWP1 and WWP2 therapeutically holds promise for cancer treatment.
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