Academic Journal
A conformation selective mode of inhibiting SRC improves drug efficacy and tolerability ; Running title: New mode of inhibiting SRC improves drug properties
| العنوان: | A conformation selective mode of inhibiting SRC improves drug efficacy and tolerability ; Running title: New mode of inhibiting SRC improves drug properties |
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| المؤلفون: | Temps, Caroline, Lietha, Daniel, Webb, Emily R., Li, Xue-Feng, Dawson, John C., Muir, Morwenna, Macleod, Kenneth G., Valero, Teresa, Munro, Alison F., Contreras-Montoya, Rafael, Luque-Ortega, Juan Román, Fraser, Craig, Beetham, Henry, Schoenherr, Christina, Lopalco, Maria, Arends, Mark J., Frame, Margaret C., Qian, Bin-Zhi, Brunton, Valerie G., Carragher, Neil O., Unciti-Broceta, Asier |
| المساهمون: | University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, CSIC - Centro de Investigaciones Biológicas Margarita Salas (CIB), Universidad de Granada, Wellcome Trust, Lietha, Daniel, Webb, Emily R., Li, Xue-Feng, Muir, Morwenna, Luque-Ortega, Juan Román, Beetham, Henry, Schoenherr, Christina, Arends, Mark J., Frame, Margaret C., Carragher, Neil O., Unciti-Broceta, Asier |
| بيانات النشر: | American Association for Cancer Research |
| سنة النشر: | 2021 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | SRC kinase, Inactive conformation, Kinase inhibitors, Breast cancer, Metastasis |
| الوصف: | 14 p.-5 fig. ; Despite 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 unprecedented 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 novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders. ; C.T. thanks the CMVM of the University of Edinburgh (Principal's scholarship). D.L. 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.W., J.C.D. and K.G.M. are funded by CRUK. J.R.L.O. acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T.V. is funded by H2020-MSCA-IF-2016-749299. RCM thanks the support from the Vice Rectorate for Research of the University of Granada. X.-F.L. and B.-Z.Q. are funded by a CRUK Career Development Fellowship (C49791/A17367). B.-Z.Q. also acknowledges support from an ERC Starting Grant (716379). C.S, M.C.F. and V.G.B are funded by CRUK Programme Grant C157/A15703. N.O.C. and A.U.B are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3). ; Peer reviewed |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0008-5472 1538-7445 |
| Relation: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-099318-B-I00; info:eu-repo/grantAgreement/EC/H2020/749299; Publisher's version; https://doi.org/10.1158/0008-5472.CAN-21-0613; Sí; Cancer Research 81: 5438-50 (2021); http://hdl.handle.net/10261/251621; http://dx.doi.org/10.13039/100004440; http://dx.doi.org/10.13039/501100000780; http://dx.doi.org/10.13039/501100006393; http://dx.doi.org/10.13039/501100000848 |
| DOI: | 10.1158/0008-5472.CAN-21-0613 |
| DOI: | 10.13039/100004440 |
| DOI: | 10.13039/501100000780 |
| DOI: | 10.13039/501100006393 |
| DOI: | 10.13039/501100000848 |
| الاتاحة: | http://hdl.handle.net/10261/251621 https://doi.org/10.1158/0008-5472.CAN-21-0613 https://doi.org/10.13039/100004440 https://doi.org/10.13039/501100000780 https://doi.org/10.13039/501100006393 https://doi.org/10.13039/501100000848 |
| Rights: | open |
| رقم الانضمام: | edsbas.AF50DB66 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00085472 15387445 |
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| DOI: | 10.1158/0008-5472.CAN-21-0613 |