Evaluating p97 Inhibitor Analogues for Potency against p97-p37 and p97-Npl4-Ufd1 Complexes.
Evaluating p97 Inhibitor Analogues for Potency against p97-p37 and p97-Npl4-Ufd1 Complexes.
复制标题
DOI：
10.1002/cmdc.201600036
复制
发表时间：
2016-05-06
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
我们之前发现p97辅因子p47显着降低了一些ATP竞争性p97抑制剂的效力，例如2-（2-氨基-1H苯并[d]咪唑-1-基）-N-苯甲基-8-甲氧基喹唑啉-4-胺（ML 240）和2-（2 H-苯并[B][1，4]恶嗪-4（3 H）-基）-N-苯甲基-5，6，7，8四氢喹唑啉-4-胺（ML 241）。在本研究中，我们的目的是评估针对两种另外的p97辅因子复合物p97-p37和p97-Npl 4-Ufd 1的抑制剂效力。我们专注于这两种辅因子复合物，因为p37的蛋白质序列与p47有50%的相同性，并且Np 14-Ufd 1异源二聚体（NU）是研究最多的p97辅因子复合物。我们筛选了200种p97抑制剂类似物，以确定它们抑制单独p97以及p97-p37和p97-NU复合物的ATP酶活性的能力。与p47的作用相反，p37和NU没有显著改变大多数化合物的效力。这些结果突出了p97辅因子在影响p97构象和抑制剂对p97复合物的影响方面与单独p97相比的差异。需要继续努力来推进复合物特异性p97抑制剂的开发。我们对p97-p37和p97-Npl 4-Ufd 1复合物的200种p97/VCP抑制剂类似物进行了SAR研究。我们的研究为开发p97-p97辅因子复合物特异性抑制剂提供了潜在的起点。
We previously found that the p97 cofactor, p47, significantly decreased the potency of some ATP-competitive p97 inhibitors such as 2-(2-amino-1Hbenzo[d]imidazol-1-yl)-N-benzyl-8-methoxyquinazolin-4-amine (ML240) and 2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8 tetrahydroquinazolin-4-amine (ML241). In this study, we aimed to evaluate inhibitor potencies against two additional p97 cofactor complexes, p97-p37 and p97-Npl4-Ufd1. We focused on these two cofactor complexes, because the protein sequence of p37 is 50% identical to p47, and the Npl4-Ufd1 heterodimer (NU) is the most-studied p97 cofactor complex. We screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of p97 alone and of p97-p37 and p97-NU complexes. In contrast to the effect of p47, p37 and NU did not significantly change the potencies of most of the compounds. These results highlight differences among p97 cofactors in influencing p97 conformation and effects of inhibitors on p97 complexes, as compared to p97 alone. Continued efforts are needed to advance the development of complex-specific p97 inhibitors. We carried out an SAR study of 200 p97/VCP inhibitor analogues for the p97-p37 and p97-Npl4-Ufd1 complexes. Our studies provide potential starting points for developing p97-p97 cofactor complex-specific inhibitors.