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dc.contributor.authorTemps, Carolin
dc.contributor.authorValero Griñán, María Teresa 
dc.date.accessioned2021-11-22T10:03:28Z
dc.date.available2021-11-22T10:03:28Z
dc.date.issued2021-08-20
dc.identifier.citationTemps, C... [et al.] (2021). A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability. Cancer Research, 81(21), 5438-5450. DOI: [10.1158/0008-5472.CAN-21-0613]es_ES
dc.identifier.urihttp://hdl.handle.net/10481/71659
dc.descriptionC. Temps thanks the CMVM of the University of Edinburgh (Principal's scholarship). D. Lietha acknowledges support from the Spanish Ministry of Science, Innovation, and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00, cofunded by the European Regional Development Fund (FEDER). E.R. Webb, J.C. Dawson, and K.G. Macleod are funded by CRUK. J.R. Luque-Ortega acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T. Valero is funded by H2020-MSCA-IF-2016-749299. R. Contreras-Montoya thanks the support from the Vice-Rectorate for Research of the University of Granada. X-F. Li and B-Z. Qian are funded by a CRUK Career Development Fellowship (C49791/A17367). B-Z. Qian also acknowledges support from an ERC Starting Grant (716379). C. Schoenherr, M.C. Frame, and V.G. Brunton are funded by CRUK Programme Grant C157/A15703. N.O. Carragher and A. Unciti-Broceta are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3). We thank the ALBA synchrotron-radiation facility (Barcelona, Spain) for providing access for X-ray diffraction data collection and the XALOC beamline staff for their assistance.es_ES
dc.description.abstractDespite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This mechanism of action resulted in highly potent and selective pathway inhibition in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders. Significance: Small molecule–mediated inhibition of SRC impairing both catalytic and scaffolding functions confers increased anticancer properties and tolerability compared with other SRC/ABL inhibitors.es_ES
dc.description.sponsorshipSpanish Ministry of Science, Innovation, and Universities RTI2018-099318-B-I00es_ES
dc.description.sponsorshipEuropean Commissiones_ES
dc.description.sponsorshipCancer Research UKes_ES
dc.description.sponsorshipMolecular Interactions Facility funds at the CIB-CSICes_ES
dc.description.sponsorshipVice-Rectorate for Research of the University of Granadaes_ES
dc.description.sponsorshipCRUK Career Development Fellowship C49791/A17367es_ES
dc.description.sponsorshipEuropean Research Council (ERC) 716379es_ES
dc.description.sponsorshipCRUK Programme Grant C157/A15703es_ES
dc.description.sponsorshipCMVM of the University of Edinburghes_ES
dc.description.sponsorshipWellcome Trustes_ES
dc.description.sponsorshipEuropean Commission H2020-MSCA-IF-2016-749299es_ES
dc.language.isoenges_ES
dc.publisherAmerican Association for Cancer Researches_ES
dc.rightsAtribución 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.titleA Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerabilityes_ES
dc.typejournal articlees_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/716379es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/749299es_ES
dc.rights.accessRightsopen accesses_ES
dc.identifier.doi10.1158/0008-5472.CAN-21-0613
dc.type.hasVersionVoRes_ES


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