Structure Report for: 6R8Q

Atkinson, B.N., Steadman, D., Zhao, Y., Sipthorp, J., Vecchia, L., Ruza, R.R., Jegnathan, F., Lines, G., Frew, S., Monaghan, A., Kjaer, S., Bictash, M., Jones, Y., Fish, P.V.

Title: Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen
Atkinson BN, Steadman D, Zhao YG, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S and Jones EY <6 more author(s)> Atkinson BN, Steadman D, Zhao YG, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S, Monaghan A, Kjaer S, Bictash M, Jones Y, Fish PV, Zhao Y, Jones EY (- 6)
Ref: Medchemcomm, 10:1361, 2019 : PubMed
Abstract


ESTHER: Atkinson_2019_Medchemcomm_10_1361
PubMedSearch: Atkinson 2019 Medchemcomm 10 1361
PubMedID: 31534655
Gene_locus related to this paper: human-NOTUM
Inhibitor(s) related to this paper: Isoquinoline-45-JV8, Benzotriazole-39-JV5, JVB, CHEMBL4539054

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 muM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 muM) and isoquinoline 45 (IC50 0.085 muM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to 3. 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.