dc.contributor.author | Antolin, AA | |
dc.contributor.author | Ameratunga, M | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Al-Lazikani, B | |
dc.date.accessioned | 2020-03-04T10:11:21Z | |
dc.date.issued | 2020-02-17 | |
dc.identifier.citation | Scientific reports, 2020, 10 (1), pp. 2585 - ? | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3524 | |
dc.identifier.eissn | 2045-2322 | |
dc.identifier.doi | 10.1038/s41598-020-59074-4 | |
dc.description.abstract | Polypharmacology 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.format | Electronic | |
dc.format.extent | 2585 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Piperazines | |
dc.subject | Piperidines | |
dc.subject | Indazoles | |
dc.subject | Phthalazines | |
dc.subject | Indoles | |
dc.subject | Isoenzymes | |
dc.subject | Protein-Serine-Threonine Kinases | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | Proto-Oncogene Proteins | |
dc.subject | Antineoplastic Agents | |
dc.subject | Binding Sites | |
dc.subject | Protein Structure, Secondary | |
dc.subject | Protein Binding | |
dc.subject | Substrate Specificity | |
dc.subject | Protein-Tyrosine Kinases | |
dc.subject | Protein Interaction Domains and Motifs | |
dc.subject | HEK293 Cells | |
dc.subject | Molecular Docking Simulation | |
dc.subject | Polypharmacology | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Poly (ADP-Ribose) Polymerase-1 | |
dc.title | The kinase polypharmacology landscape of clinical PARP inhibitors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-01-21 | |
rioxxterms.versionofrecord | 10.1038/s41598-020-59074-4 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-02-17 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Scientific reports | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 10 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Computational Biology and Chemogenomics | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
dc.contributor.icrauthor | Banerji, Udai | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Al-Lazikani, Bissan | |