A Novel Small Molecule Inhibitor of FAK and IGF-1R Protein Interactions Decreases Growth of Human Esophageal Carcinoma

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 17, 14 Issues, 2017

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Institut de Chimie de Clermont-Ferrand
Université Clermont Auvergne

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A Novel Small Molecule Inhibitor of FAK and IGF-1R Protein Interactions Decreases Growth of Human Esophageal Carcinoma

Anti-Cancer Agents in Medicinal Chemistry, 11(7): 629-637.

Author(s): Deniz A. Ucar, Audrey Cox, Di-Hua He, David A. Ostrov, Elena Kurenova and Steven N Hochwald.

Affiliation: P.O. Box 100109, 1600 SW Archer Road, Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610.


Introduction: Esophageal cancer remains an aggressive disease with poor survival rates. FAK and IGF-1R are two important tyrosine kinases important for cell survival signaling and found to be upregulated in esophageal cancer. Our hypothesis is that a novel small molecule compound that disrupts FAK and IGF-1R protein-protein interactions (PPIs) would decrease the growth of human esophageal cancer. Methods: The compound INT2-31 (NSC344553) was identified from a virtual high throughput screen to bind to FAK and disrupt PPIs. The in vitro effects of this compound, +/- 5-FU chemotherapy, on cell signaling, viability and apoptosis in human esophageal cancer cells (KYSE 70, 140) and a direct esophageal cancer xenograft was evaluated. Results: INT2-31 caused a disruption of PPIs between FAK and IGF-1R starting at a concentration of 1μM. It also caused a dose dependent inhibition of cell viability and induction of apoptosis at low micromolar doses. These effects were associated with decreased AKT and ERK1/ERK2 phosphorylation. INT2-31 treatment, when administered via IP injection, at 50mg/kg, resulted in an in vivo decrease in tumor growth in a direct xenograft. Furthermore, treatment with 5-FU chemotherapy combined with INT2-31 resulted in a synergistic increase in apoptosis and decrease in tumor growth compared to 5-FU or INT2-31 alone. Conclusions: A novel compound that disrupts the PPIs of FAK and IGF-1R results in decreased tumor proliferation and increased apoptosis. These effects appear to be mediated through downregulation of p-AKT and p-ERK. This compound deserves further study as a novel treatment strategy in patients with esophageal cancer.


Cancer, cell survival, esophageal cancer, esophagus, FAK, IGF-1R, Esophageal Carcinoma, FAK-GST, subcutaneously, intracytoplasmic.

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Article Details

Volume: 11
Issue Number: 7
First Page: 629
Last Page: 637
Page Count: 9
DOI: 10.2174/187152011796817718
Price: $58
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