The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that plays a critical role in malignant transformation, mitogenic growth, survival and metastasis in breast and other cancers. As such it is a promising target for anti-cancer drug development. Our long term goal is to employ novel small molecule inhibitors of the IGF-1R to block the activation of the downstream events that promote cancer growth. As the IGF-1R is implicated in resistance of tumors to chemotherapy, radiation, and anti-hormone treatment, we hypothesize that IGF-1 R inhibitors will provide effective agent in adjuvant therapy. In a recent publication, we have demonstrated that, in breast cancer cells, diaryl urea (DAU) compounds inhibit the IGF-1 R, as well as the IGF-1 R signaling pathway, that this inhibition induces cell cycle arrest and apoptosis, and that DAU compounds inhibit tumor growth in a mouse model of breast cancer. We have expanded our understanding of the structure function relationship of DAU and the receptor target, and have modeled the interaction of our preliminary lead DAU into the ATP binding site of the receptor kinase domain. In our proposed studies we will first characterize the mechanisms and specificity of DAU interactions with the IGF-1 R and the resultant cellular effects. In these studies we will test our hypothesis that DAUs are acting as specific inhibitors of ATP binding to the IGF-1 R through biochemical analysis of IGF-1 R inhibition and by crystallizing and analyzing the structure of the DAU-IGF-1R complex. We will employ high throughput genomics and microarray analysis to identify alternate targets of DAUs. We will characterize the therapeutic potential of small molecule inhibitors by exploring their ability to overcome common tumor phenotypes associated with resistance to drugs that target other RTKs, and by studying the ability of DAUs to block key aspects of metastasis: the loss of cell to cell adhesion and cellular invasion and establishment of tumors in secondary tissues. Concurrently, we will employ knowledge gained on the specific interactions between the active DAU compounds and the IG-1R in order to synthesize, screen, and characterize new compounds with increased affinity for the IGF- 1 R. We will characterize the specificity of novel analogs for the IGF-1 R vs. other kinases, and characterize the biological effects of altering the specificity of DAUs for the IGF-1 R. Together these studies will result in the production of well-characterized DAU-based compounds for anti-cancer drug development.
|Troib, Ariel; Landau, Daniel; Youngren, Jack F et al. (2011) The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease. Growth Horm IGF Res 21:285-91|
|Engen, William; O'Brien, Terrence E; Kelly, Brendan et al. (2010) Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R). Bioorg Med Chem 18:5995-6005|