Abstract
Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.
Highlights
INTRODUCTION TO WNT SIGNALINGDuring development and adult homeostasis, cells use secreted proteins to communicate and coordinate their activities
Lee and co-workers used a combination of structure-based drug design (SBDD), molecular modeling, and virtual screening to construct a focused-library to screen for inhibitors against the Wnt-binding site of the extracellular FZD8 cysteine-rich domain (CRD).[67]
Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult
Summary
During development and adult homeostasis, cells use secreted proteins to communicate and coordinate their activities. Lee and co-workers used a combination of structure-based drug design (SBDD), molecular modeling, and virtual screening to construct a focused-library to screen for inhibitors against the Wnt-binding site of the extracellular FZD8 cysteine-rich domain (CRD).[67] This approach led to a small collection of compounds, exemplified by NSC654259 (15), that displayed single digit micromolar activity in a Wnt 3a-dependent reporter assay in 3T3 cells. Using a HTS campaign with a TCF/LEF Cell sensor reporter assay, Han et al identified a range of fused heterocyclic compounds as potent inhibitors of Notum (Figure 6).[115] The initial lead carboxylic acid 31 was selected for further development with modifications of the carboxyl group, the tricyclic core and substitution of the aromatic rings. This structural information may guide the design of more potent Notum inhibitors
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