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dc.contributor.authorNarvaez, AJen
dc.contributor.authorBer, Sen
dc.contributor.authorCrooks, Aen
dc.contributor.authorEmery, Amyen
dc.contributor.authorHardwick, Ben
dc.contributor.authorGuarino Almeida, Een
dc.contributor.authorHuggins, Daviden
dc.contributor.authorPerera, Den
dc.contributor.authorRoberts-Thomson, Men
dc.contributor.authorAzzarelli, Robertaen
dc.contributor.authorHood, FEen
dc.contributor.authorPrior, IAen
dc.contributor.authorWalker, DWen
dc.contributor.authorBoyce, Ren
dc.contributor.authorBoyle, RGen
dc.contributor.authorBarker, SPen
dc.contributor.authorTorrance, CJen
dc.contributor.authorMcKenzie, GJen
dc.contributor.authorVenkitaraman, Ashoken
dc.date.accessioned2017-09-25T14:41:00Z
dc.date.available2017-09-25T14:41:00Z
dc.date.issued2017-08-10en
dc.identifier.issn2451-9456
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/267376
dc.description.abstractMutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis. PLK1 or PLK4 depletion recapitulates these cellular effects, as does PBD overexpression, corroborating Poloppin's mechanism of action. An optimized analog with favorable pharmacokinetics, Poloppin-II, is effective against KRAS-expressing cancer xenografts. Poloppin resistance develops less readily than to an ATP-competitive PLK1 inhibitor; moreover, cross-sensitivity persists. Poloppin sensitizes mutant KRAS-expressing cells to clinical inhibitors of c-MET, opening opportunities for combination therapy. Our findings exemplify the utility of small molecules modulating the protein-protein interactions of PLKs to therapeutically target mutant KRAS-expressing cancers.
dc.description.sponsorshipAll authors, except R.A., D.W.W., R.B., R.G.B., F.E.H., I.A.P., S.P.B., and C.J.T., were supported by Medical Research Council program grants MC_UU_12022/1 and MC_UU_12022/8 to A.R.V. North West Cancer Research supported I.A.P. and F.E.H. Innovate UK funded the development of Poloppin-II by PhoreMost Ltd. (Biomedical Catalyst grant no. 102140). R.A. was supported by MRC research grant MR/K018329/1 and the Rosetrees Trust.
dc.languageengen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectPLK1en
dc.subjectPLK4en
dc.subjectPPI inhibitoren
dc.subjectPolo-box domainen
dc.subjectPolo-like kinaseen
dc.subjectc-METen
dc.subjectcancer therapyen
dc.subjectmutant KRASen
dc.subjectprotein-protein interactionsen
dc.titleModulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRASen
dc.typeArticle
prism.endingPage1028.e7
prism.issueIdentifier8en
prism.publicationDate2017en
prism.publicationNameCell Chemical Biologyen
prism.startingPage1017
prism.volume24en
dc.identifier.doi10.17863/CAM.13358
dcterms.dateAccepted2017-07-07en
rioxxterms.versionofrecord10.1016/j.chembiol.2017.07.009en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-08-10en
dc.contributor.orcidHuggins, David [0000-0003-1579-2496]
dc.identifier.eissn2451-9448
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12022/1_do not transfer?)
pubs.funder-project-idMRC (MC_UU_12022/8)
pubs.funder-project-idMedical Research Council (MC_UU_12022/1)
pubs.funder-project-idMRC (MR/K018329/1)
pubs.funder-project-idMRC (MR/L007266/1)
pubs.funder-project-idMRC (MC_UU_12022/8)
cam.issuedOnline2017-08-10en


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International