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dc.contributor.authorMeyers, Jen_US
dc.contributor.authorChessum, NEAen_US
dc.contributor.authorAli, Sen_US
dc.contributor.authorMok, NYen_US
dc.contributor.authorWilding, Ben_US
dc.contributor.authorPasqua, AEen_US
dc.contributor.authorRowlands, Men_US
dc.contributor.authorTucker, MJen_US
dc.contributor.authorEvans, LEen_US
dc.contributor.authorRye, CSen_US
dc.contributor.authorO'Fee, Len_US
dc.contributor.authorLe Bihan, Y-Ven_US
dc.contributor.authorBurke, Ren_US
dc.contributor.authorCarter, Men_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorBrown, Nen_US
dc.contributor.authorvan Montfort, RLMen_US
dc.contributor.authorJones, Ken_US
dc.contributor.authorCheeseman, MDen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2018-11-19T12:37:00Z
dc.date.issued2018-12-13en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30613326en_US
dc.identifier.citationACS Med Chem Lett, 2018, 9 (12), pp. 1199 - 1204en_US
dc.identifier.issn1948-5875en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2946
dc.identifier.doi10.1021/acsmedchemlett.8b00364en_US
dc.description.abstractPolypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ligand CCT245232 (2), to establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily polypharmacology for our kinase inhibitor, despite little overall sequence identity. The interfamily polypharmacology of 2 with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library despite no apparent ligand or binding site similarity. Our data demonstrates that in areas of drug discovery where intrafamily polypharmacology is often an issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding interfamily polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries.en_US
dc.format.extent1199 - 1204en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titlePrivileged Structures and Polypharmacology within and between Protein Families.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-11-16en_US
rioxxterms.versionofrecord10.1021/acsmedchemlett.8b00364en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-12-13en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfACS Med Chem Letten_US
pubs.issue12en_US
pubs.notesNo embargoen_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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 (including Analytical Chemistry)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublished onlineen_US
pubs.volume9en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMedicinal Chemistry 1 (including Analytical Chemistry)en_US
icr.researchteamMedicinal Chemistry 3en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorCheeseman, Matthewen_US
dc.contributor.icrauthorMeyers, Joshuaen_US
dc.contributor.icrauthorLe Bihan, Yann-Vaien_US
dc.contributor.icrauthorBurke, Rosemaryen_US
dc.contributor.icrauthorBlagg, Julianen_US
dc.contributor.icrauthorVan Montfort, Roberten_US
dc.contributor.icrauthorJones, Keithen_US


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