Craig Fraser

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Neil O. Carragher

Edinburgh Cancer Research

Carolin Temps

Edinburgh Cancer Research

Emily R. Webb

Edinburgh Cancer Research

Margaret C. Frame

University of Edinburgh

Bin‐Zhi Qian

Fudan University Shanghai Cancer Center

Asier Unciti‐Broceta

Edinburgh Cancer Research

Daniel Lietha

Consejo Superior de Investigaciones Científicas

John C. Dawson

Edinburgh Cancer Research

Teresa Valero

Universidad de Granada

Morwenna Muir

Edinburgh Cancer Research

Cooperative Institutions

Edinburgh Cancer Research

University of Edinburgh

MRC Institute of Genetics and Molecular Medicine

Western General Hospital

Cancer Research UK

Medical Research Council

Universidad de Granada

Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Institute of Molecular Genetics

Garvan Institute of Medical Research

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

Carolin Temps Daniel Lietha Emily R. Webb Xuefeng Li John C. Dawson

<div>Abstract<p>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 <i>in vivo</i>. 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.</p>Significance:<p>Small molecule–mediated inhibition of SRC impairing both catalytic and scaffolding functions confers increased anticancer properties and tolerability compared with other SRC/ABL inhibitors.</p></div>

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10.1158/0008-5472.c.6513090.v1

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Introductory note to 1930c and 1931a

Springer eBooks (2013)

Craig Fraser

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10.1007/978-3-540-70856-8_14

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