Show simple item record

dc.contributor.authorAntolin, AA
dc.contributor.authorAmeratunga, M
dc.contributor.authorBanerji, U
dc.contributor.authorClarke, PA
dc.contributor.authorWorkman, P
dc.contributor.authorAl-Lazikani, B
dc.date.accessioned2020-03-04T10:11:21Z
dc.date.issued2020-02-17
dc.identifier.citationScientific reports, 2020, 10 (1), pp. 2585 - ?
dc.identifier.issn2045-2322
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.
dc.formatElectronic
dc.format.extent2585 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectPiperazines
dc.subjectPiperidines
dc.subjectIndazoles
dc.subjectPhthalazines
dc.subjectIndoles
dc.subjectIsoenzymes
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectCyclin-Dependent Kinases
dc.subjectProto-Oncogene Proteins
dc.subjectAntineoplastic Agents
dc.subjectBinding Sites
dc.subjectProtein Structure, Secondary
dc.subjectProtein Binding
dc.subjectSubstrate Specificity
dc.subjectProtein-Tyrosine Kinases
dc.subjectProtein Interaction Domains and Motifs
dc.subjectHEK293 Cells
dc.subjectMolecular Docking Simulation
dc.subjectPolypharmacology
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectPoly (ADP-Ribose) Polymerase-1
dc.titleThe kinase polypharmacology landscape of clinical PARP inhibitors.
dc.typeJournal Article
dcterms.dateAccepted2020-01-21
rioxxterms.versionofrecord10.1038/s41598-020-59074-4
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-02-17en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScientific reports
pubs.issue1
pubs.notesNot known
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.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-statusPublished
pubs.volume10en_US
pubs.embargo.termsNot known
icr.researchteamComputational Biology and Chemogenomicsen_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
dc.contributor.icrauthorAl-Lazikani, Bissanen
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorWorkman, Paulen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorAntolin Hernandez, Alberten


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

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