Tain compounds with improved membrane permeability. Most biological processes are regulated by reversible phosphorylation, and kinases play a central role in signal transmission. Kinases buy 1627709-94-7 interconnect different signalling pathways in time and space, and confer flexibility to the regulation and coordination of multiple biological processes including cell division, apoptosis and survival among others. Furthermore, alteration in kinase 912656-34-9 function is a common underlying process to many pathological situations including cancer, inflammation, and neurodegeneration. The elucidation of the human kinome has opened up new possibilities to characterize and develop strategies to manipulate these regulatory processes with therapeutic aims. Kinase domains are very suitable for development of specific inhibitors, some of which have already been applied in cancer treatment, both for tyrosine kinases, such as PDGF/kit with imatinib in a variety of tumours, or to Ser-Thr kinases such as for B-Raf in melanomas. Kinase domains in an inactive state are more structurally diverse than their activated form. However, the main problem in development of specific inhibitors resides in the high conservation of the catalytic domain, which reduces the specificity of most inhibitors by targeting several kinases simultaneously, which makes them non specific. This crossinhibition results in a significant promiscuity, which can be the cause of unexpected side effects in clinical use. The inhibition promiscuity of a kinase can be predicted based on the conservation of specific residues within the kinase fold. The VRK kinase family received its name from vaccinia virus B1R, its unique kinase required for viral replication. The VRK family has a unique ortholog in C. elegans and D. Melanogaster, but is composed of three proteins in mammals, a similar situation to the p53 family that has only one member in invertebrates and three members in mammals, which reflects the evolution of regulatory mechanisms as the organisms become more complex. These kinases in the human kinome belong to a unique and isolated subfamily with only three proteins VRK that very early, and near the kinases common trunk, diverged from the branch that much later led to casein kinase I family. In addition, the VRK proteins have unique substitutions suggesting they might be pseudokinases. VRK1 and VRK2 are two novel Ser-Thr kinases that have a common catalytic domain with a fifty-three percent homology, and play a role in cell division processes. However, VRK1 and VRK2 have been demonstrated to be catalytically active; while VRK3, the most divergent of the three, is catalytically inactive. Interestingly, the kinase activity of VRK1 and VRK2 proteins can be regulated by allosteric protein-protein interactions; they are both
