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Fragment-Based Drug Design of Novel Pyranopyridones as Cell Active and Orally Bioavailable Tankyrase Inhibitors
Javier de Vicente1, Parcharee Tivitmahaisoon1, Pamela Berry1
1Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
Abstract:
Tankyrase activity has been linked to the regulation of intracellular axin levels, which have been shown to be crucial for the Wnt pathway. Deregulated Wnt signaling is important for the genesis of many diseases including cancer. We describe herein the discovery and development of a new series of tankyrase inhibitors. These pyranopyridones are highly active in various cell-based assays. A fragment/structure based optimization strategy led to a compound with good pharmacokinetic properties that is suitable for in vivo studies and further development.
Insights
Researchers developed novel pyranopyridone tankyrase inhibitors crucial for Wnt pathway regulation. These compounds show high activity in cell assays and good properties for further development in disease, including cancer.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Tankyrase regulates intracellular axin levels, a key component of the Wnt signaling pathway.
- Aberrant Wnt signaling is implicated in the development of various diseases, notably cancer.
Purpose of the Study:
- To discover and develop a new series of potent tankyrase inhibitors.
- To identify compounds with favorable pharmacokinetic properties for in vivo studies.
Main Methods:
- Fragment and structure-based drug design and optimization.
- Cell-based assays to evaluate inhibitor activity.
- Pharmacokinetic profiling of lead compounds.
Main Results:
- A novel series of pyranopyridone compounds targeting tankyrase were synthesized.
- These compounds demonstrated high activity in cell-based assays.
- Optimization yielded a compound with suitable pharmacokinetic properties for further preclinical development.
Conclusions:
- The developed pyranopyridones represent promising tankyrase inhibitors.
- The lead compound is suitable for in vivo studies and further therapeutic development.
- This work contributes to the potential treatment of Wnt-pathway-driven diseases, including cancer.
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