Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 17, Pages 9464-9483Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00660
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Funding
- Alzheimer's Research UK (ARUK)
- Francis Crick Institute
- Eli Lilly
- Alzheimer's Research UK [520909]
- Cancer Research UK [FC001002, C375/A17721]
- UK Medical Research Council [FC001002]
- Wellcome Trust [FC001002]
- UCL Innovative Therapeutics Postdoctoral Training Programme - Eli Lilly
- EPSRC UCL IAA
- Wellcome Trust - Wellcome Centre for Human Genetics, University of Oxford [203141/Z/16/Z]
- EPSRC [EP/P020410/1, EP/K005030/1] Funding Source: UKRI
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The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
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