Given that activation of P2X and P2Y receptors requires eATP in the micromolar range, isolated effects of eATP mediated by purinergic receptor signal ing are unlikely to contribute to the experimental results obtained from our model. We have clearly shown that ATP is tightly bound to VEGF A165 and a critical concentration of ATP above 1. 8 nM is required for bioactivity. Imatinib Mesylate IC50 Based on these results, Inhibitors,Modulators,Libraries the VEGF A165 ATP complex and not VEGF A165 by itself appears to be the active ligand causing the proliferative effects under cell culture conditions. Both VEGF A165 ATP complex formation and the putative interaction with its receptor remain to be elucidated in vivo. Conclusions For the first time we provided ample evidence that ATP binds to VEGF A165.

Binding of ATP most Inhibitors,Modulators,Libraries likely involves basic residues within the heparin binding domain and constitutes a prerequisite for the prolifera tive activity of VEGF A165. Background Protein kinases comprise a large family of membrane bound and cytosolic enzymes, with 518 genes identified in the human genome. All protein kinases catalyze the transfer of the phosphate of adenosine triphosphate to the hydroxyl group of tyrosine, serine, or threo nine residues of protein substrates. Together with the protein phosphotases, kinases act as regulatory switches for essentially all cellular processes, including metabolic pathways, cell growth, differentiation, survival, and apop tosis. Abnormal function of protein kinases leads to development of many serious diseases, such as cancer, diabetes, inflammatory and autoimmune disorders, and diseases of the heart.

In Inhibitors,Modulators,Libraries particular, many cancers may be linked with increased activity of specific growth factor receptor tyrosine kinases due to overexpression, or mutations leading to constitutively active forms. Great hopes were placed that inhibition of dysfunc tional kinases will lead to new highly effective therapies. The first small molecule kinase inhibitor, imatinib, was launched in 2001 as an anticancer agent for the treatment of chronic myeloid leukemia. its action being to inhibit the constitutively active form of Abelson tyrosine kinase. Since then, eight compounds targeting the kinase catalytic domain were approved for treatment of various forms of cancer. over thirty kinase inhibitors are in the clinical phases of development, and many more are in preclinical pipelines.

A major problem in the development of Inhibitors,Modulators,Libraries kinase inhibi tors is to achieve specificity. Most of the kinase Inhibitors,Modulators,Libraries inhibitors in current development interact with the kinases ATP binding cleft, where they compete with ATP. How ever, the ATP binding site is highly conserved among all kinases and it is therefore difficult to design a drug selec tive for scientific study only one kinase at a time. Other functional domains that have been exploited to target kinases are also conserved among numerous kinases making the design of selective inhibitors problematic also in these cases.