Targeting of the protein interaction site between FAK and IGF-1R.
The interaction of focal adhesion kinase (FAK) and insulin-like growth factor-1 receptor (IGF-1R) plays an important role in cancer cell survival. Targeting this interaction with small molecule drugs could be a novel strategy in cancer therapy. By a series of pull-down assays using GST-tagged FAK fragments and His-tagged IGF-1R intracellular fragments, we showed that the FAK-NT2 (a.a. 127-243) domain directly interacts with the N-terminal part of the IGF-1R intracellular domain. Overexpressed FAK-NT2 domain was also shown to co-localize with IGF-1R in pancreatic cells. Computational modeling was used to predict the binding configuration of these two domains and to screen for small molecules binding to the interaction site. This strategy successfully identified a lead compound that disrupts FAK/IGF-1R interaction.
Zheng
Donghang
D
Department of Surgery, University of Florida, Gainesville, FL, USA.
Kurenova
Elena
E
Ucar
Deniz
D
Golubovskaya
Vita
V
Magis
Andrew
A
Ostrov
David
D
Cance
William G
WG
Hochwald
Steven N
SN
D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human