Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen.

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-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC₅₀ 33 μM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC₅₀ 0.032 μM) and isoquinoline 45 (IC₅₀ 0.085 μM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structu

SUBMITTER: Atkinson BN 

PROVIDER: S-EPMC6727465 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature