RT Journal Article
T1 A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability.
A1 Temps, Carolin
A1 Lietha, Daniel
A1 Webb, Emily R
A1 Li, Xue-Feng
A1 Dawson, John C
A1 Muir, Morwenna
A1 Macleod, Kenneth G
A1 Valero, Teresa
A1 Munro, Alison F
A1 Contreras-Montoya, Rafael
A1 Luque-Ortega, Juan R
A1 Fraser, Craig
A1 Beetham, Henry
A1 Schoenherr, Christina
A1 Lopalco, Maria
A1 Arends, Mark J
A1 Frame, Margaret C
A1 Qian, Bin-Zhi
A1 Brunton, Valerie G
A1 Carragher, Neil O
A1 Unciti-Broceta, Asier
AB 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. 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.
YR 2021
FD 2021-08-20
LK https://hdl.handle.net/10668/24919
UL https://hdl.handle.net/10668/24919
LA en
DS RISalud
RD Apr 5, 2025