6T2H

Furano[2,3-d]prymidine amides as Notum inhibitors

Summary for 6T2H

• Entry DOI: 10.2210/pdb6t2h/pdb
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, DIMETHYL SULFOXIDE, SULFATE ION, ... (7 entities in total)
• Functional Keywords: substrate, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 45702.73

Authors

Zhao, Y.,Jones, E.Y. (deposition date: 2019-10-08, release date: 2020-01-01, Last modification date: 2024-11-06)

Primary citation

Atkinson, B.N.,Steadman, D.,Mahy, W.,Zhao, Y.,Sipthorp, J.,Bayle, E.D.,Svensson, F.,Papageorgiou, G.,Jeganathan, F.,Frew, S.,Monaghan, A.,Bictash, M.,Jones, E.Y.,Fish, P.V.
Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.
Bioorg.Med.Chem.Lett., 30:126751-126751, 2020

PubMed Abstract: The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.

PubMed: 31862412
DOI: 10.1016/j.bmcl.2019.126751

Experimental method

X-RAY DIFFRACTION (1.41 Å)