2411969-39-4

ARUK3001185 is an inhibitor of palmitoleoyl-protein carboxylesterase NOTUM (IC₅₀ = 6.7 nM), an enzyme involved in the deacylation of Wnt.¹ It is selective for NOTUM over a panel of 39 serine hydrolases and 485 kinases, including casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), at 10 μM and a panel of 47 receptors, ion channels, transporters, and enzymes at 30 μM, but does inhibit the serotonin (5-HT) receptor subtype 5-HT_3A, α4β2 subunit-containing nicotinic acetylcholine receptors (nAChRs), and monoamine oxidase A (MAO-A; IC₅₀s = 4.5, 10, and 28 μM, respectively). ARUK3001185 prevents NOTUM-induced decreases in Wnt3a signaling in a cell-based reporter assay (EC₅₀ = 110 nM).

ARUK3001185 (Compound 8l) is a potent, selective, orally active and brain-penetrant inhibitor of Notum activity with an IC50 of 6.7 nM[1].

1. Willis, N.J., Mahy, W., Sipthorp, J., et al. Design of a potent, selective, and brain-penetrant inhibitor of Wnt-deactivating enzyme notum by optimization of a crystallographic fragment hit J. Med. Chem. 65(10),7212-7230(2122).