As suggested by the promiscuity score in which VRK1 and VRK2 are the kinases with the likelihood of having the most specific inhibitors. This prediction was also confirmed in a different experimental approach based on the determination on the kinase specificity of current inhibitors. VRK1 has been identified as a drugable kinase in rhabdomyosarcoma and breast cancer. The pattern of VRK1 and VRK2 inhibition suggests that they might be structurally closer to cdk1 than any other kinases, but even so, they maintain large differences. However, the high concentrations needed to achieve some inhibition means that none of the inhibitors tested can be used to inhibit VRK proteins in cell based assays, since they will also affect several other kinases. Kinase activation implies a conformational change involving the activation loop that has a DFG motif in an out or in state. These alternative conformations might affect the kinase response to inhibitors. In the DFG 
out or inactive state, the kinase might bind and prevent the activating conformational change, rather than displacing ATP in case of competitive inhibitors. Thus, depending on the conformation the effect may vary. On the other hand, in the active state, competitive inhibitors will displace the nucleotide. In vivo the situation is likely to be a mixture of different situations. VRK1 inhibition by TDZD-8, a non competitive inhibitor of GSK3b, might be a GW786034 particular case. The TDZD-8 effect on VRK1 activity seems to be an all or none effect at a specific concentration. This might reflect the switch between two alternative VRK1 conformations when the inhibitor reaches a critical threshold concentration. It would be interesting to know if TDZD-8 is acting by maintaining a loop out conformation for its activation loop that has some peculiarities. The identification and validation of specific inhibitors for human VRK proteins and vaccinia B1R have the potential of clinical applications. In this context, development of specific inhibitors for VRK1 and VRK2 is a real AG-013736 possibility because they are likely to be highly specific. Since these kinases have been implicated in response to growth factors and in DNA damage response, their inhibitors can make cells more sensitive to current chemotherapeutic drugs or irradiation, reducing the toxicity associated with them, since kinase inhibitors have shown to be well tolerated by patients. Use of kinase inhibitors for treatment of acute infection by poxviruses, such as smallpox, might be an alternative therapy for acute viral infection by reducing viral replication. The development of such specific inhibitors is a real possibility that needs to be pursued once the structure of these proteins and lead compounds become available. Microvascular pericytes are cells of mesenchymal origin situated juxtaposition to the endothelial layer in the microvasculature i.e. capillaries, venules and small arterioles. They are continuous with the vascular basement membrane. Pericytes have a central role in the structural and functional integrity of the microvascular bed in resting tissues. Their equivalents in larger vessels are smooth muscle cells. During development and in adult activated tissues they are important modulators of the angiogenic process where they regulate vascular regression, pruning and vessel maturation during tissue remodeling. Pericytes also play a role in promoting platelet aggregation. Thus pericytes, in addition to endothelial cells, must also be tightly controlled in order to maintain tissue homeostasis, optimize tissue repair and regeneration.