AZD4547

Preclinical pharmacology

AZD4547 is a potent inhibitor of FGFR-1,2 and 3 (IC50 < 5nM) with weaker activity against FGFR-4 (IC50 165nM), KDR (24nM) , MARKs (60nM), and IGF1R (581nM) of 73 other kinases  screened.  In cell-lines, overexpressing the relevant receptor, AZD4547 potently inhibits the kinase activity of FGFR 1-3 (IC50 <50nM), while again be weaker for KDR (IC50 258nM) and IGF1R (IC50 829 ± 40nM). AZD4547 was shown to inhibit proliferation, in a dose-dependent manner, in several cancer cell-lines, known to overexpress fibroblast growth factor (FGF) receptors. In KMS11, KG1a and SUM52PE cell-lines, AZD4547 inhibited FGFR tyrosyl phosphorylation and the phosphorylation of the downstream signalling molecules p42/p44MAP kinases.

Oral treatment of mice bearing KMS11 (myeloma) xenografts, either once or twice daily with AZD4547 resulted in dose-dependent tumour growth inhibition. AZD4547 similarly induced inhibition of tumour growth in mice bearing KG1a (leukemic) xenografts.