更新于：2024-11-01

CK1 x VRK1

更新于：2024-11-01

基本信息

关联

项与 CK1 x VRK1 相关的药物

CK1δ/CK1ε/VRK1 inhibitors(Aché Laboratórios Farmacêuticos)

靶点

CK1δ x CK1ε x VRK1

作用机制

CK1δ抑制剂 [+2]

在研机构

Aché Laboratórios Farmacêuticos SA

原研机构

Aché Laboratórios Farmacêuticos SA

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

CK1/VRK1 inhibitors(Aché Laboratórios Farmacêuticos)

靶点

CK1 x VRK1

作用机制

CK1抑制剂 [+1]

在研机构

Federal University of Santa Catarina

原研机构

Aché Laboratórios Farmacêuticos SA

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CK1 x VRK1 相关的临床结果

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100 项与 CK1 x VRK1 相关的转化医学

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0 项与 CK1 x VRK1 相关的专利（医药）

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项与 CK1 x VRK1 相关的文献（医药）

2024-06-13·Journal of Medicinal Chemistry

Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε

Article

作者: Ferreira, Marcos A ; Elkins, Jonathan M ; Teodoro, Bruno V M ; Cunha, Micael R ; Balourdas, Dimitrios-Ilias ; Urien, Bruno ; Gileadi, Carina ; Lemmens, Bennie B L G ; Massirer, Katlin B ; Vasconcelos, Stanley N S ; Dutra, Luiz A ; de Souza Gama, Fernando H ; Knapp, Stefan ; Couñago, Rafael M ; Azevedo, Hatylas ; Nilsson, Ann-Sofie ; Hawgood, Michael ; Ramos, Priscila Z ; Dos Reis, Caio Vinícius ; Serafim, Ricardo A M ; Gileadi, Opher ; Mueller, Susanne ; Almeida, Vitor M ; Mascarello, Alessandra ; Guimarães, Cristiano R W ; Takarada, Jéssica Emi ; Santiago, André S ; Salmazo, Anita

Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.

2016-04-12·Oncotarget

Survival kinase genes present prognostic significance in glioblastoma

Article

作者: Guan, Ting ; Franck, Christopher T. ; Liang, Yanping ; Sheng, Zhi ; Varghese, Robin T. ; Kelly, Deborah F.

Cancer biomarkers with a strong predictive power for diagnosis/prognosis and a potential to be therapeutic targets have not yet been fully established. Here we employed a loss-of-function screen in glioblastoma (GBM), an infiltrative brain tumor with a dismal prognosis, and identified 20 survival kinase genes (SKGs). Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that the expression of CDCP1, CDKL5, CSNK1E, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 stratified GBM prognosis with or without temozolomide (TMZ) treatment as a covariate. For the first time, we found that GBM patients with a high level of NEK9 and PIK3CB had a greater chance of having recurrent tumors. The expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary GBM tumors was associated with recurrence-related prognosis. Notably, the level of PIK3CB in recurrent tumors was much higher than that in newly diagnosed ones. Congruent with these results, genes in the PI3K/AKT pathway showed a significantly strong correlation with recurrence rate, further highlighting the pivotal role of PIK3CB in the disease progression. Importantly, 17 SKGs together presented a novel GBM prognostic signature. SKGs identified herein are associated with recurrence rate and present prognostic significance in GBM, thereby becoming attractive therapeutic targets.

2008-10-01·Journal of Biological Chemistry2区 · 生物学

A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection

2区 · 生物学

Article

作者: Nicola J MacLaine ; Pedro A Lazo ; David W Meek ; Jennifer A Fraser ; Bodil Øster ; Tedd R Hupp ; Per Höllsberg ; Carolyn Buckner ; Bettina Bundgaard

The tumor suppressor protein p53 is activated by distinct cellular stresses including radiation, hypoxia, type I interferon, and DNA/RNA virus infection. The transactivation domain of p53 contains a phosphorylation site at Ser20 whose modification stabilizes the binding of the transcriptional co-activator p300 and whose mutation in murine transgenics induces B-cell lymphoma. Although the checkpoint kinase CHK2 is implicated in promoting Ser20 site phosphorylation after irradiation, the enzyme that triggers this phosphorylation after DNA viral infection is undefined. Using human herpesvirus 6B (HHV-6B) as a virus that induces Ser20 site phosphorylation of p53 in T-cells, we sought to identify the kinase responsible for this virus-induced p53 modification. The p53 Ser20 kinase was fractionated and purified using cation, anion, and dye-ligand exchange chromatography. Mass spectrometry identified casein kinase 1 (CK1) and vaccinia-related kinase 1 (VRK1) as enzymes that coeluted with virus-induced Ser20 site kinase activity. Immunodepletion of CK1 but not VRK1 removed the kinase activity from the peak fraction, and bacterially expressed CK1 exhibited Ser20 site kinase activity equivalent to that of the virus-induced native CK1. CK1 modified p53 in a docking-dependent manner, which is similar to other known Ser20 site p53 kinases. Low levels of the CK1 inhibitor D4476 selectively inhibited HHV-6B-induced Ser20 site phosphorylation of p53. However, x-ray-induced Ser20 site phosphorylation of p53 was not blocked by D4476. These data highlight a central role for CK1 as the Ser20 site kinase for p53 in DNA virus-infected cells but also suggest that distinct stresses may selectively trigger different protein kinases to modify the transactivation domain of p53 at Ser20.