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dc.contributor.authorBoffey, Helen K
dc.contributor.authorRooney, Timothy
dc.contributor.authorWillems, Henriette
dc.contributor.authorEdwards, Simon
dc.contributor.authorGreen, Christopher
dc.contributor.authorHoward, Tina
dc.contributor.authorOgg, Derek
dc.contributor.authorRomero, Tamara
dc.contributor.authorScott, Duncan
dc.contributor.authorWinpenny, David
dc.contributor.authorDuce, James
dc.contributor.authorSkidmore, John
dc.contributor.authorClarke, Jonathan
dc.contributor.authorAndrews, Stephen
dc.date.accessioned2022-02-25T00:30:28Z
dc.date.available2022-02-25T00:30:28Z
dc.date.issued2022-02-24
dc.identifier.issn0022-2623
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334446
dc.description.abstractPhosphatidylinositol 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.
dc.format.mediumPrint-Electronic
dc.publisherAmerican Chemical Society (ACS)
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleDevelopment of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.
dc.typeArticle
dc.publisher.departmentC.I.M.R. Division of Translational Medicine
dc.date.updated2022-02-24T08:46:19Z
prism.numberacs.jmedchem.1c01819
prism.publicationDate2022
prism.publicationNameJ Med Chem
dc.identifier.doi10.17863/CAM.81861
rioxxterms.versionofrecord10.1021/acs.jmedchem.1c01819
rioxxterms.versionAM
dc.contributor.orcidRooney, Timothy [0000-0001-6788-5526]
dc.contributor.orcidWillems, Henriette [0000-0001-7196-5975]
dc.contributor.orcidScott, Duncan [0000-0003-1917-9576]
dc.contributor.orcidSkidmore, John [0000-0001-9108-7858]
dc.contributor.orcidClarke, Jonathan [0000-0002-4079-5333]
dc.contributor.orcidAndrews, Stephen [0000-0001-6021-6899]
dc.identifier.eissn1520-4804
rioxxterms.typeJournal Article/Review
pubs.funder-project-idAlzheimer's Research UK (ARUK-2015DDI-CAM)
cam.issuedOnline2022-02-11
cam.orpheus.success2022-02-24 - Embargo set during processing via Fast-track
cam.depositDate2022-02-24
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-02-11


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