Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.
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Authors
Boffey, Helen K
Willems, Henriette MG
Edwards, Simon
Green, Christopher
Howard, Tina
Ogg, Derek
Romero, Tamara
Winpenny, David
Duce, James
Publication Date
2022-02-24Journal Title
J Med Chem
ISSN
0022-2623
Publisher
American Chemical Society (ACS)
Number
acs.jmedchem.1c01819
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Boffey, H. K., Rooney, T. P., Willems, H. M., Edwards, S., Green, C., Howard, T., Ogg, D., et al. (2022). Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.. J Med Chem, (acs.jmedchem.1c01819) https://doi.org/10.1021/acs.jmedchem.1c01819
Abstract
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kβ. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.
Sponsorship
Alzheimer's Research UK (ARUK-2015DDI-CAM)
Embargo Lift Date
2023-02-11
Identifiers
External DOI: https://doi.org/10.1021/acs.jmedchem.1c01819
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334446
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