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. 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.
Subject(s)
Bone Neoplasms/drug therapy , Breast Neoplasms/drug therapy , Focal Adhesion Kinase 1/antagonists & inhibitors , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Small Molecule Libraries/pharmacology , src-Family Kinases/antagonists & inhibitors , Animals , Apoptosis , Bone Neoplasms/metabolism , Bone Neoplasms/secondary , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Protein Conformation , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , src-Family Kinases/chemistry , src-Family Kinases/metabolismABSTRACT
Unsymmetrical functionalised cyanine dyes, covering the whole colour range, were readily synthesised (in 100 mg amounts) by a combination of microwave and solid-phase methodologies.