Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen123. Issue 8 (16th May 2019)

• Record Type: Journal Article
• Authors: Atkinson, Benjamin N.; Steadman, David; Zhao, Yuguang; Sipthorp, James; Vecchia, Luca; Ruza, Reinis R.; Jeganathan, Fiona; Lines, Georgie; Frew, Sarah; Monaghan, Amy; Kjær, Svend; Bictash, Magda; Jones, E. Yvonne; Fish, Paul V.
• Is Part Of: MedChemComm. Volume 10:Issue 8(2019)
• Page Start: 1361
• Page End: 1369
• Publication Date: 2019-05-16
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c9md00096h
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : Optimization of fragment hit3 identified isoquinoline45 as a potent inhibitor of NOTUM with an unexpected flipped binding mode. Abstract : NOTUM is a carboxylesterase that has been shown to act by mediating the O -depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 μM). Optimization of hit3 by SAR studies guided by SBDD identified indazole38 (IC50 0.032 μM) and isoquinoline45 (IC50 0.085 μM) as potent inhibitors of NOTUM. The binding of45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to3 . However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.