Inhibition of Fgf-1 Receptor Tyrosine Kinase Activity by Pd 161570, a New Protein-Tyrosine Kinase Inhibitor

Abstract Through direct synthetic efforts we discovered a small molecule which is a 40 nanomolar inhibitor of the human FGF-1 receptor tyrosine kinase. 1-Tert-butyl-3-[6-(2,6-dichloro-phenyl)-2-(4- diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea (PD 161570) had about 5- and 100-fold greater selectivity toward the FGF-1 receptor (IC 50 = 40 nM) compared with the PDGFβ receptor (IC 50 = 262 nM) or EGF receptor (IC 50 = 3.7 μM) tyrosine kinases, respectively. In addition, PD 161570 suppressed constitutive phosphorylation of the GF-1 receptor in both human ovarian carcinoma cells (A121(p)) and Sf9 insect cells overexpressing the human FGF-1 receptor and blocked the growth of A121(p)) cells in culture. The results demonstrate a novel synthetic inhibitor with nanomolar potency and specificity towards the FGF-1 receptor tyrosine kinase.