Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening.
Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening.
复制标题
DOI：
10.1021/jm100331d
复制
发表时间：
2010-10-14
影响因子：
7.3
通讯作者：
Newton AC
中科院分区：
文献类型：
--
作者：
Sierecki E;Sinko W;McCammon JA;Newton AC
PH结构域富含亮氨酸重复蛋白磷酸酶（PHLPP）直接使Akt和蛋白激酶C去磷酸化和失活，使其成为两种主要存活途径的药物干预的主要靶点。在这里，我们报告的发现，小分子抑制剂的磷酸酶活性的PHLPP，PP2C家族的磷酸酶的成员，没有一般的药理学抑制剂。首先，在体外筛选NCI的多样性集对纯化的PHLPP 2磷酸酶结构域的抑制。其次，将来自开放的NCI数据库的选定文库对接到PHLPP 2磷酸酶结构域的虚拟模型中，该模型先前用我们的实验数据集训练，揭示了其他抑制剂。生物化学和细胞测定导致鉴定出两种结构不同的化合物，其在体外选择性地抑制PHLPP，增加细胞中的Akt信号传导，并防止细胞凋亡。因此，化学和虚拟筛选导致鉴定了通过抑制其负调节因子PHLPP来促进Akt信号传导的小分子。
PH domain Leucine-rich repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C, poising it as a prime target for pharmacological intervention of two major survival pathways. Here we report on the discovery of small molecule inhibitors of the phosphatase activity of PHLPP, a member of the PP2C family of phosphatases for which there are no general pharmacological inhibitors. First, the Diversity Set of the NCI was screened for inhibition of the purified phosphatase domain of PHLPP2 in vitro. Second, selected libraries from the open NCI database were docked into a virtual model of the phosphatase domain of PHLPP2, previously trained with our experimental data set, unveiling additional inhibitors. Biochemical and cellular assays resulted in the identification of two structurally diverse compounds that selectively inhibit PHLPP in vitro, increase Akt signaling in cells, and prevent apoptosis. Thus, chemical and virtual screening has resulted in the identification of small molecules that promote Akt signaling by inhibiting its negative regulator PHLPP.
登录
查看更多内容
影响因子：
15.9
作者：
Bernal-Mizrachi, E;Wen, W;Permutt, MA
通讯作者：
Permutt, MA
影响因子：
7.3
作者：
Kontoyianni, M;McClellan, LM;Sokol, GS
通讯作者：
Sokol, GS
影响因子：
10.9
作者：
Elghazi, Lynda;Bernal-Mizrachi, Ernesto
通讯作者：
Bernal-Mizrachi, Ernesto
影响因子：
16
作者：
Brognard, John;Sierecki, Emma;Newton, Alexandra C.
通讯作者：
Newton, Alexandra C.
影响因子：
15.9
作者：
Bernal-Mizrachi, E;Fatrai, S;Permutt, MA
通讯作者：
Permutt, MA