2478 The pyrimidopyrimidine moiety represents a core structure that is a useful template for the design of a variety of tyrosine kinase inhibitors. From high throughput screening, a pyrimidopyrimidine analogue was identified as a dual inhibitor of the growth factor receptors KDR (IC50 = 40 nM) and FGFR-1 (IC50 = 210 nM). This analogue was a significantly less potent inhibitor of other kinases tested (LCK, IC50 = 8 μM; CDK2 and p38, IC50 > 25 μM). The crystal structure of the src-family tyrosine kinase LCK with a closely related analogue bound was determined, elucidating the binding mode of the pyrimidopyrimidines. From these data, the ligand was docked into the ATP binding pocket of KDR. Based on this model a series of analogues were designed and synthesized to study the structure activity relationship. These compounds showed excellent activity in in vitro kinase assays and also in growth-factor stimulated HUVEC proliferation assays. In vivo experiments demonstrated significant inhibition of angiogenesis in the corneal pocket assay (CPA) and tumor growth inhibition in xenograft models for a number of these compounds. Structure activity relationship of these pyrimidopyrimidine compounds will be discussed.