Other inhibitors, KU 55933, NU7026 and t IC86621 had no significant effect on VRK1 Kinaseaktivit Or VRK2A One of the main consequences of the VRK proteins Is their m Possible use for development Develop specific inhibitors, which are used in cancer therapy may k. But the main problem with the current inhibitors is that they usually simultaneously on several related kinases, although there are differences in affinity Can be t. In practice, this means that the clinical application of kinase JNJ 26854165 Serdemetan inhibitors that cross could pose a significant risk of uncontrollable side effects Strips. Another approach to identify specific targeting kinases, is the use of siRNA specific kinase. VRK proteins, probably because the effect was examined within 48 hours what. Not suitable for very stable protein with a half-life of four to six days VRK1 However one Restrict Restriction kinases removable at very stable proteins such VRKs as in the experiments of RNA interference observation erm Glicht reducing the RNA, but not the protein level.
Knockdown of VRK1 and VRK2 has already provided information on processes that selectively affected by their specific inhibition be Nnten k. Knockdown VRK1 results in a block in the G1 cell cycle progression before Descr Nkungspunkt, it can be used under conditions where the proliferation is a part of its pathogenesis. LY315920 For VRK2, influenced his knockdown MAPK because VRK2 module signaling through direct interaction with scaffolding proteins Like JIP1 affect response to hypoxia or cytokines and affect KSR1 oncogene signaling. On the basis of their structural differences and VRK2 VRK1 kinases predicted proteins With a very low index of Promiskuit t and insensitive to kinase inhibitors available.
Model VRK inhibitors best demonstrated in this study justified This prediction and has two main features. First, human VRK1 and VRK2 and vaccinia B1R generally very sensitive to the panel of inhibitors tested in the present study that target fill a variety of human kinases with an IC50 in the nanomolar range in most cases. Most of them have little or no effect on the kinase VRK even at a high concentration, making it. Unsuitable for use in vivo The second feature is that for some compounds detected inhibition does not answer a particular subtype of kinases. Among the inhibitors identified bad, there is a clear distinction between model and VRK1 VRK2. VRK1 is more sensitive to staurosporine and RO 31 8220, two inhibitors of PKC, w During VRK2 is more sensitive to Cdk1 inhibitor roscovitine and two inhibitors of CDK1.
Interestingly, Cdk1 inhibitor has been shown to also interact with the two kinases, but only VRK2 activity Was inhibited t. For all inhibitors its sensitivity is defined by three size Enordnungen kinases in comparison to their reduced preferably targeted. Further inhibitor proteins for VRK show some sensitivity AZD7762 CHK1 and CHK2 that goal with a lot of hours Heren affinity t. Although VRK2 are less effective and locked VRK1 of AZD7762, the IC50 for five size Enordnungen hours ago Than that of CHK1 and CHK2 inhibition required. Sun IC261 CK1 inhibits 6 micromolar, Similar to the inhibition of VRK2, but has no effect on the activity of t VRK1.