6ZVL
ARUK3000263 complex with Notum
Summary for 6ZVL
| Entry DOI | 10.2210/pdb6zvl/pdb |
| Related | 6ZUV |
| Descriptor | Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | notum, inhibitor, wnt, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 44655.53 |
| Authors | |
| Primary citation | Mahy, W.,Willis, N.J.,Zhao, Y.,Woodward, H.L.,Svensson, F.,Sipthorp, J.,Vecchia, L.,Ruza, R.R.,Hillier, J.,Kjaer, S.,Frew, S.,Monaghan, A.,Bictash, M.,Salinas, P.C.,Whiting, P.,Vincent, J.P.,Jones, E.Y.,Fish, P.V. 5-Phenyl-1,3,4-oxadiazol-2(3 H )-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit. J.Med.Chem., 63:12942-12956, 2020 Cited by PubMed Abstract: Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of identified oxadiazol-2-one as a preferred example with properties consistent with drug-like chemical space. Screening in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit into lead (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling. PubMed: 33124429DOI: 10.1021/acs.jmedchem.0c01391 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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