American Association for Cancer Research
Browse
- No file added yet -

Supplementary Data from A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Download (94.95 kB)
dataset
posted on 2023-03-31, 04:24 authored by Carolin Temps, Daniel Lietha, Emily R. Webb, Xue-Feng Li, John C. Dawson, Morwenna Muir, Kenneth G. Macleod, Teresa Valero, Alison F. Munro, Rafael Contreras-Montoya, Juan R. Luque-Ortega, Craig Fraser, Henry Beetham, Christina Schoenherr, Maria Lopalco, Mark J. Arends, Margaret C. Frame, Bin-Zhi Qian, Valerie G. Brunton, Neil O. Carragher, Asier Unciti-Broceta
Supplementary Data from A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Funding

College of Medicine and Veterinary Medicine, University of Edinburgh

Ministerio de Ciencia, Innovación y Universidades (MCIU)

Cancer Research UK (CRUK)

Consejo Superior de Investigaciones Científicas (CSIC)

European Commission (EC)

Universidad de Granada (UGR)

European Research Council (ERC)

Wellcome Trust Centre for Mitochondrial Research (WCMR)

History

ARTICLE ABSTRACT

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 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. Small molecule–mediated inhibition of SRC impairing both catalytic and scaffolding functions confers increased anticancer properties and tolerability compared with other SRC/ABL inhibitors.

Usage metrics

    Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC