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Structural Analysis and Development of Notum Fragment Screening Hits.

Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L, Ruza RR, Harlos K, Jeganathan F, Constantinou S, Costa A, Kjær S, Bictash M, Salinas PC, Whiting P, Vincent JP, Fish PV, Jones EY
ACS Chem Neurosci 13 2060-2077 (2022)

Cited: 3 times
EuropePMC logo PMID: 35731924

Abstract

The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1

Reviews - 7bd3 mentioned but not cited (1)

  1. Compounds Inhibiting Noppera-bo, a Glutathione S-transferase Involved in Insect Ecdysteroid Biosynthesis: Novel Insect Growth Regulators. Ebihara K, Niwa R. Biomolecules 13 461 (2023)

Articles - 7bd3 mentioned but not cited (1)

  1. Structural Analysis and Development of Notum Fragment Screening Hits. Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L, Ruza RR, Harlos K, Jeganathan F, Constantinou S, Costa A, Kjær S, Bictash M, Salinas PC, Whiting P, Vincent JP, Fish PV, Jones EY. ACS Chem Neurosci 13 2060-2077 (2022)


Articles citing this publication (1)

  1. Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway. Liu Y, Chen H, Xiao L, Dong P, Ma Y, Zhou Y, Yang J, Bian B, Xie G, Chen L, Shen L. Cell Oncol (Dordr) (2023)


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