Abstract A245: Imidazo[2,1-b]thiazole and imidazo[1,2-a]pyridine amides as novel inhibitors of the insulin-like growth factor (IGF1R) and members of the epidermal growth factor family of tyrosine kinases

• Published in: Molecular cancer therapeutics 2009-12, Vol.8 (12_Supplement), p.A245-A245
• Main Authors: Fidanze, Steve D., Erickson, Scott A., Hubbard, Robert D., Wang, Gary T., Mantei, Robert A., BaMaung, Nwe Y., Clark, Richard F., Sorensen, Bryan K., Kovar, Peter, Pappano, William, Zhang, Qian, Wilsbacher, Julie L., Hu, Xiaoming, Tucker, Lora A., Cheng, Min, Swinger, Kerren K., Stewart, Kent D., Wang, Jieyi, Bell, Randy L., Davidsen, Steven K., Sheppard, George S.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-A245

The insulin-like growth factor 1 receptor (IGF1R) and its ligands, IGF1 and IGF2 are associated with cell growth and resistance to apoptosis. The ErbB axis, consisting of 4 receptor tyrosine kinases (EGFR, ErbB2, ErbB3, and ErbB4) is a longstanding target of cancer chemotherapy. There is a growing body of literature suggesting that targeting a combination of the IGF and ErbB axes would be more effective than targeting either alone. A screen of Abbott's compound collection revealed a scaffold, the imidazothiazoles, which showed activity against EGFR. A similar scaffold from the literature had previously been reported to have IGF1R activity. Optimization of the imidazothiazoles, and a scaffold hop to imidazopyridines, has provided a series of compounds with amide head groups with kinase inhibitory activity against IGF1R, EGFR, and ErbB2. These compounds also demonstrated inhibition of p-IGF1R and p-EGFR in a human epidermoid carcinoma line (A-431), as well as inhibition of p-ErbB2 in a human gastric cancer cell line (N87). This poster will discuss the synthesis and optimization of the imidazothiazoles and imidazopyridines as multitargeted kinase inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A245.