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

Carolin Temps, Daniel Leitha, Emily Webb, Xue-Feng Li, John C Dawson, Morwenna Muir, Kenneth Macleod, Teresa Valero, Alison 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 CarragherAsier Unciti-Broceta

Research output: Contribution to journalArticlepeer-review

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 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.
Original languageEnglish
JournalCancer Research
Early online date20 Aug 2021
DOIs
Publication statusE-pub ahead of print - 20 Aug 2021

Keywords

  • SRC kinase
  • inactive conformation
  • kinase inhibitors
  • breast cancer
  • metastasis

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