ChemDiv’s NOTUM (Wnt Signaling) Library consists of over 4,000 compounds.
NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Members of the Wnt family are secreted signaling proteins that play key roles in adult stem cell biology as well as in embryonic development.
Conversely, dysregulation of Wnt signaling is frequently associated with growth-related pathologies and cancers, particularly those of tissues for which Wnts normally stimulate self-renewal and repair. Wnt signaling is also implicated to have a role in neurodegenerative diseases such as Alzheimer’s disease. O-Palmitoleoylation of a conserved serine residue in Wnt proteins is a key post-translation modification required for efficient binding of Wnt proteins to Frizzled receptors, a requirement for signal transduction.
A carboxylesterase NOTUM was previously shown to antagonize Wnt signaling pathways. More recently, NOTUM has been shown to act by mediating the depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. It follows that inhibition of NOTUM could restore Wnt signaling with potential benefit in diseases where Wnt deficiency is an underlying cause.
 B. N. Atkinson et al., “Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen,” Medchemcomm, vol. 10, no. 8, pp. 1361–1369, 2019, doi: 10.1039/c9md00096h.
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