Receptor tyrosine kinases (RTKs) utilize ATP to autophosphorylate specific tyrosine residues in the sequence of proteins. A variety of tumors have dysfunctional RTKs, often overexpressed, and result in inappropriate signaling. Thus inhibition of RTKs have provided a new paradigm for cancer chemotherapy and several RTK inhibitors are currently in clinical trials as antitumor agents. We recently discovered a series of novel RTK inhibitors which have exceptional single, dual and multi- inhibitory effects against RTKs. In addition, we also discovered a separate series of novel analogs which possess potent RTK inhibitory activity, antiangiogenic activity along with dihydrofolate reductase (DHFR) inhibitory activity in single agents. On the basis of our preliminary studies, we propose to carry out a structure optimization of our lead analogs to afford the most effective agents and to provide a structure-activity relationship study (SAR).
The specific aims are to synthesize compounds to optimize inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2), against endothelial growth factor receptor (EGFR), against platelet-derived growth factor receptor-13 (PDGFR-[3). To synthesize analogs to optimize DHFR and VEGFR-2 inhibitory activity in single agents. Since some of the lead analogs have multiple inhibitory effects against more than one RTK, the SAR generated in these studies will also allow a delineation of structural requirements necessary for single or multiple inhibitory activity against RTKs. All of the compounds will be evaluated on a collaborative basis for in vitro inhibitory activity against VEGFR-2, EGFR, PDGFR-_, FGFR and the CAM assay for antiangiogenic activity (Dr. Michael ihnat) and appropriate analogs against DHFR (Dr. Roy L. Kisliuk). Appropriate analogs will also be evaluated against A431 cells that overexpress EGFR (Dr. Ihnat). In addition, we have selected three analogs from our preliminary studies for in vivo assay in the B 16 mouse melanoma tumor model for antitumor activity. At least four additional analogs from this study will be selected for in vivo evaluation (Dr. Michael Inhat). This study should provide structurally optimized analogs which function as single, dual or multitargeted inhibitors of RTKs as well as analogs for VEGFR-2 and DHFR as antitumor agents with a different spectrum of antitumor activity and perhaps afford analogs that can be advanced to clinical trials against solid tumors.
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