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dc.contributor.authorAntolin, AAen_US
dc.contributor.authorAmeratunga, Men_US
dc.contributor.authorBanerji, Uen_US
dc.contributor.authorClarke, PAen_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorAl-Lazikani, Ben_US
dc.date.accessioned2020-03-04T10:11:21Z
dc.date.issued2020-02-17en_US
dc.identifier.citationScientific reports, 2020, 10 (1), pp. 2585 - ?en_US
dc.identifier.issn2045-2322en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3524
dc.identifier.eissn2045-2322en_US
dc.identifier.doi10.1038/s41598-020-59074-4en_US
dc.description.abstractPolypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.en_US
dc.formatElectronicen_US
dc.format.extent2585 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleThe kinase polypharmacology landscape of clinical PARP inhibitors.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-01-21en_US
rioxxterms.versionofrecord10.1038/s41598-020-59074-4en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2020-02-17en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfScientific reportsen_US
pubs.issue1en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Computational Biology and Chemogenomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.publication-statusPublisheden_US
pubs.volume10en_US
pubs.embargo.termsNot knownen_US
icr.researchteamComputational Biology and Chemogenomicsen_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
dc.contributor.icrauthorAl-Lazikani, Bissanen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorBanerji, Udaien_US
dc.contributor.icrauthorAntolin Hernandez, Alberten_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/