Synthesis of novel inhibitors that target the insulin growth factor-1 receptor (IGF-1R): (potential anti-breast cancer compounds)

The insulin-like growth factor 1 receptor (IGF-1R) is a member of receptor tyrosine kinase which plays a critical role in the development of all stages of cancers, especially breast cancer which is reported to be the most common cancer among women in the United States. IGF-1R is considered to be an attractive target for the drug development for the treatment of breast cancer because it regulates the signal transduction which results in cancerous cell growth and proliferation. Developing small molecule inhibitors that interfere in IGF-1R system is our ultimate interest in our project. Here in this report, derivatives of our lead inhibitor PQ-401 is discussed. PQ-401 is a novel class of AHU inhibitor consisting of 4-aminoquinolin and a substituted aromatic ring system. The SAR of PQ-401 and the corresponding lead inhibitors was rationalized by using computational 3-D docking study, which showed the relationship among the hydrogen bonding interaction, the binding energy and the potency of inhibitors. Based on the hypothetical rationale obtained from this information, new inhibitor structures were proposed with two purposes. One is to diversify the scaffold, and another is to create hydrogen bonding contacts in the empty hinge region of ATP binding pocket. Total of eighteen inhibitor candidates were synthesized with the optimized synthetic route. The cell-based assays identified one moderately potent compound. Future in vitro characterization in pending.