8BQ4

Crystal Structure of Phosphatidylinositol 5-Phosphate 4-Kinase (PI5P4K2C) bound to an inhibitor

Summary for 8BQ4

• Entry DOI: 10.2210/pdb8bq4/pdb
• Descriptor: Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma, 6-methyl-~{N}-(4-methylsulfonylphenyl)thieno[2,3-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: lipid kinase, atp-competitive inhibitor, phosphatidylinositol 5-phosphate, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 84674.64

Authors

Ogg, D.J.,Howard, T.D. (deposition date: 2022-11-18, release date: 2022-12-28, Last modification date: 2024-02-07)

Primary citation

Rooney, T.P.C.,Aldred, G.G.,Boffey, H.K.,Willems, H.M.G.,Edwards, S.,Chawner, S.J.,Scott, D.E.,Green, C.,Winpenny, D.,Skidmore, J.,Clarke, J.H.,Andrews, S.P.
The Identification of Potent, Selective, and Brain Penetrant PI5P4K gamma Inhibitors as In Vivo-Ready Tool Molecules.
J.Med.Chem., 66:804-821, 2023

PubMed Abstract: Owing to their central role in regulating cell signaling pathways, the phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive therapeutic targets in diseases such as cancer, neurodegeneration, and immunological disorders. Until now, tool molecules for these kinases have been either limited in potency or isoform selectivity, which has hampered further investigation of biology and drug development. Herein we describe the virtual screening workflow which identified a series of thienylpyrimidines as PI5P4Kγ-selective inhibitors, as well as the medicinal chemistry optimization of this chemotype, to provide potent and selective tool molecules for further use. In vivo pharmacokinetics data are presented for exemplar tool molecules, along with an X-ray structure for ARUK2001607 () in complex with PI5P4Kγ, along with its selectivity data against >150 kinases and a Cerep safety panel.

PubMed: 36516442
DOI: 10.1021/acs.jmedchem.2c01693

Experimental method

X-RAY DIFFRACTION (2.42 Å)