1. Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity.
- Author
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Buchstaller HP, Anlauf U, Dorsch D, Kuhn D, Lehmann M, Leuthner B, Musil D, Radtki D, Ritzert C, Rohdich F, Schneider R, and Esdar C
- Subjects
- Crystallography, X-Ray, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, Tankyrases chemistry, Tankyrases metabolism, Drug Discovery, Enzyme Inhibitors pharmacology, Quinazolines pharmacology, Tankyrases antagonists & inhibitors
- Abstract
Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and WaterMap structures and resulted in compound 5k , a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of 5k in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compound in a colorectal xenograft model in vivo .
- Published
- 2019
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