Abstract
Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.
Highlights
It could be argued that this is one of those rare translational research targets where the medicinal chemistry is relatively advanced compared with the understanding of the disease biology, but the two are closely linked. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease
Dysregulation of Wnt signaling has been associated with a number of human diseases
Carboxylesterase Notum has been shown to be a negative regulator of Wnt signaling
Summary
A second lead from Lexicon’s HTS was thieno[2,3-d]pyrimidine 4. Transposition of the thiophene ring and optimization of the substituents identified 5 as a potent inhibitor. Mouse pharmacokinetic data for 5 (10 mg/kg p.o.): half-life = 8 h; oral bioavailability = 65%
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