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dc.contributor.authorFrame, S
dc.contributor.authorSaladino, C
dc.contributor.authorMacKay, C
dc.contributor.authorAtrash, B
dc.contributor.authorSheldrake, P
dc.contributor.authorMcDonald, E
dc.contributor.authorClarke, PA
dc.contributor.authorWorkman, P
dc.contributor.authorBlake, D
dc.contributor.authorZheleva, D
dc.date.accessioned2020-08-27T08:56:58Z
dc.date.issued2020-07-09
dc.identifier.citationPloS one, 2020, 15 (7), pp. e0234103 - ?
dc.identifier.issn1932-6203
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4030
dc.identifier.eissn1932-6203
dc.identifier.doi10.1371/journal.pone.0234103
dc.description.abstractCyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
dc.formatElectronic-eCollection
dc.format.extente0234103 - ?
dc.languageeng
dc.language.isoeng
dc.publisherPUBLIC LIBRARY SCIENCE
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectSulfonamides
dc.subjectCyclin-Dependent Kinases
dc.subjectAdenosine
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectCyclin-Dependent Kinase 9
dc.subjectCyclin-Dependent Kinase 2
dc.subjectCell Cycle Checkpoints
dc.subjectMyeloid Cell Leukemia Sequence 1 Protein
dc.subjectBridged Bicyclo Compounds, Heterocyclic
dc.titleFadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-05-19
rioxxterms.versionofrecord10.1371/journal.pone.0234103
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfPloS one
pubs.issue7
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/Signal Transduction & Molecular Pharmacology
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/Signal Transduction & Molecular Pharmacology
pubs.publication-statusPublished
pubs.volume15
pubs.embargo.termsNot known
icr.researchteamSignal Transduction & Molecular Pharmacology
dc.contributor.icrauthorClarke, Paul


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