更新于：2024-11-01

IKKε x PDPK1 x TBK1

更新于：2024-11-01

基本信息

关联

项与 IKKε x PDPK1 x TBK1 相关的药物

BX795

靶点

IKKε x PDPK1 x TBK1

作用机制

IKKε抑制剂 [+2]

在研机构

Berlex Biosciences

原研机构

Berlex Biosciences

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IKKε x PDPK1 x TBK1 相关的临床结果

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100 项与 IKKε x PDPK1 x TBK1 相关的转化医学

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0 项与 IKKε x PDPK1 x TBK1 相关的专利（医药）

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项与 IKKε x PDPK1 x TBK1 相关的文献（医药）

2015-11-01·Vascular Pharmacology3区 · 医学

The critical role of Akt in cardiovascular function

3区 · 医学

Review

作者: Su, Yunchao ; Abeyrathna, Prasanna

Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases.

2012-12-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Synthesis and structure–activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

4区 · 医学

Article

作者: Kristian Birchall ; Michelle Newman ; Debra Taylor ; Kristopher Clark ; William Tsang ; Stephen J. Lewis ; Jasveen Chugh ; Ahmad Kamal ; Philip Cohen ; Ela Smiljanic-Hurley ; Justin Bryans ; Thomas Drake ; Joanne Osborne ; Alison Levy ; Edward G. McIver ; J. Simon C. Arthur

The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

2011-04-19·Proceedings of the National Academy of Sciences1区 · 综合性期刊

IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation

1区 · 综合性期刊

Article

作者: Zhao, Bin ; Zhang, Denghong ; You, Ming ; Lu, Min-Kan ; Condorelli, Gianluigi ; Xie, Xiaoduo ; Guan, Kun-Liang ; Wang, Cun-Yu

AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor −/− cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.