Differential inhibitor sensitivity between human kinases VRK1 and VRK2.
Differential inhibitor sensitivity between human kinases VRK1 and VRK2.
复制标题
DOI：
10.1371/journal.pone.0023235
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lazo PA
中科院分区：
文献类型：
--
作者：
Vázquez-Cedeira M;Barcia-Sanjurjo I;Sanz-García M;Barcia R;Lazo PA
人牛痘相关激酶（VRK 1和VRK 2）是涉及控制细胞周期进入、凋亡和自噬的非典型活性Ser-Thr激酶，并影响丝裂原活化蛋白激酶（MAPK）的信号传导。VRK催化位点的特定结构差异使其成为开发特异性抑制剂的合适候选物。在这项工作中，我们已经确定了VRK 1和VRK 2激酶抑制剂的敏感性，目前用于生物测定或临床前研究，以区分这两种蛋白质以及相对于牛痘病毒B1 R激酶。VRK蛋白和牛痘B1 R均被靶向Src、MEK 1、B-Raf、JNK、p38、CK 1、ATM、CHK 1/2和DNA-PK的不同类型的抑制剂抑制得很差，并且它们中的大多数甚至在100 µM时也没有效果。尽管它们的灵敏度低，但这些抑制剂中的一些在低微摩尔范围内能够区分VRK 1、VRK 2和B1 R。VRK 1对星形孢菌素、RO-31-8220和TDZD 8更敏感。VRK 2对roscovitine、RO 31-8220、Cdk 1抑制剂、AZD 7762和IC 261更敏感。牛痘病毒B1 R对星形孢菌素、KU 55933和RO 31-8220更敏感，但对IC 261不敏感。因此，这三种激酶对激酶抑制剂的敏感性不同。这种对已知抑制剂的差异反应可以为VRK 1或VRK 2特异性抑制剂提供低交叉抑制或无交叉抑制的结构框架。高度特异性VRK 1抑制剂的开发可能在这些激酶鉴定具有较差预后的临床亚型的癌症中具有潜在的临床用途，如乳腺癌中VRK 1的情况。
Human vaccinia-related kinases (VRK1 and VRK2) are atypical active Ser-Thr kinases implicated in control of cell cycle entry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK). The specific structural differences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we have determined the sensitivity of VRK1 and VRK2 to kinase inhibitors, currently used in biological assays or in preclinical studies, in order to discriminate between the two proteins as well as with respect to the vaccinia virus B1R kinase. Both VRK proteins and vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2 and DNA-PK, and most of them have no effect even at 100 µM. Despite their low sensitivity, some of these inhibitors in the low micromolar range are able to discriminate between VRK1, VRK2 and B1R. VRK1 is more sensitive to staurosporine, RO-31-8220 and TDZD8. VRK2 is more sensitive to roscovitine, RO 31–8220, Cdk1 inhibitor, AZD7762, and IC261. Vaccinia virus B1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present a different pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structural framework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1 inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorer prognosis, as is the case of VRK1 in breast cancer.
登录
查看更多内容
影响因子：
3.7
作者：
BANHAM, AH;SMITH, GL
通讯作者：
SMITH, GL
影响因子：
7.2
作者：
Khoury, Marie P.;Bourdon, Jean-Christophe
通讯作者：
Bourdon, Jean-Christophe
DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan
DOI：
10.1006/bbrc.1993.1936
发表时间：
1993-08-16
影响因子：
3.1
作者：
KELLER, HU;NIGGLI, V
通讯作者：
NIGGLI, V
影响因子：
5.3
作者：
Kang, Tae-Hong;Park, Do-Young;Kim, Kyong-Tai
通讯作者：
Kim, Kyong-Tai