dc.contributor.author | Moore, AS | |
dc.contributor.author | Faisal, A | |
dc.contributor.author | Mak, GWY | |
dc.contributor.author | Miraki-Moud, F | |
dc.contributor.author | Bavetsias, V | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | Box, G | |
dc.contributor.author | Hallsworth, A | |
dc.contributor.author | de Haven Brandon, A | |
dc.contributor.author | Xavier, CPR | |
dc.contributor.author | Stronge, R | |
dc.contributor.author | Pearson, ADJ | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Chopra, R | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Taussig, DC | |
dc.contributor.author | Linardopoulos, S | |
dc.date.accessioned | 2020-05-26T11:13:18Z | |
dc.date.issued | 2020-04-14 | |
dc.identifier.citation | Blood advances, 2020, 4 (7), pp. 1478 - 1491 | |
dc.identifier.issn | 2473-9529 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3633 | |
dc.identifier.eissn | 2473-9537 | |
dc.identifier.doi | 10.1182/bloodadvances.2019000986 | |
dc.description.abstract | Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs. | |
dc.format | Print | |
dc.format.extent | 1478 - 1491 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-02-11 | |
rioxxterms.versionofrecord | 10.1182/bloodadvances.2019000986 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Blood advances | |
pubs.issue | 7 | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia | |
pubs.publication-status | Published | |
pubs.volume | 4 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Drug Target Discovery | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Acute Leukaemia | |
dc.contributor.icrauthor | Miraki-Moud, Farideh | |
dc.contributor.icrauthor | Bavetsias, Vassilios | |
dc.contributor.icrauthor | Stronge, Randal | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Linardopoulos, Spyridon | |