8C8C

Crystal Structure of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PI5P4Ka) bound to an inhibitor

Summary for 8C8C

• Entry DOI: 10.2210/pdb8c8c/pdb
• Descriptor: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha, ~{N}-(3-chloranyl-4-methoxy-phenyl)-7-(3,4-dimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: inhibitor, atp, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43238.24

Authors

Harborne, S.P.D.,Howard, T.D.,Ogg, D.T. (deposition date: 2023-01-19, release date: 2023-04-26, Last modification date: 2024-06-19)

Primary citation

Willems, H.M.G.,Edwards, S.,Boffey, H.K.,Chawner, S.J.,Green, C.,Romero, T.,Winpenny, D.,Skidmore, J.,Clarke, J.H.,Andrews, S.P.
Identification of ARUK2002821 as an isoform-selective PI5P4K alpha inhibitor.
Rsc Med Chem, 14:934-946, 2023

PubMed Abstract: The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders. Many of the PI5P4Kα inhibitors that have been reported to date have suffered from poor selectivity and/or potency and the availability of better tool molecules would facilitate biological exploration. Herein we report a novel PI5P4Kα inhibitor chemotype that was identified through virtual screening. The series was optimised to deliver ARUK2002821 (36), a potent PI5P4Kα inhibitor (pIC = 8.0) which is selective other PI5P4K isoforms and has broad selectivity against lipid and protein kinases. ADMET and target engagement data are provided for this tool molecule and others in the series, as well as an X-ray structure of 36 solved in complex with its PI5P4Kα target.

PubMed: 37252102
DOI: 10.1039/d3md00039g

Experimental method

X-RAY DIFFRACTION (2.096 Å)