A review on kinases phosphorylating the carboxyl-terminal domain of RNA polymerase II—Biological functions and inhibitors

Zhang, Jianru; Zhang, Xiaoyun; Huang, Hua; Ding, Yaozhong

doi:10.1016/j.bioorg.2020.104318

Cited by 7 publications

(5 citation statements)

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“…Hypoxia is a strong stimulus for PH. Alveolar hypoxia induces excessive proliferation of vSMCs that remodels pulmonary vascular wall [ 1 , 36 , 42 , 45 , 52 – 54 , 58 ]. Since PLK1 is crucial in mitosis and PLK1 deficiency reduces cell proliferation/viability [ 11 – 13 , 15 – 17 ], we speculated that PLK1 might play an essential role in the proliferation–apoptosis imbalance of PH.…”

Section: Discussionmentioning

confidence: 99%

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Polo-like kinase 1 promotes pulmonary hypertension

Chen,

Wang,

Zheng

et al. 2023

Respir Res

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Background Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development. Methods Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice. Plk1 heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH. Results Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion of Plk1 were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice. Conclusions Augmented PLK1 is essential for the development of PH and is a druggable target for PH.

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Section: Discussionmentioning

confidence: 99%

“…Twenty control mice were subcutaneously injected with DMSO once per week for 3 weeks under normoxia. These mice were then treated randomly with either vehicle (n = 10) or BI 6727 (15 mg/kg body weight biweekly) (n = 10) by gavage for 3 weeks [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

Polo-like kinase 1 promotes pulmonary hypertension

Chen,

Wang,

Zheng

et al. 2023

Respir Res

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“…To confirm cellular inhibition of the kinase activity of CDKs 7 and 9, phosphorylation status of RNAP II-Ser2 and -Ser5documented phosphorylation sites for CDKs 9 and 7, respectively [8] -was examined using western blotting after oneor 24-hour treatment of MV4-11 cells with either 9 q or 9 v. Upon one-hour incubation, both compounds diminished the phosphorylation of the two serine residues greatly at their respective concentrations of 1.5 × and 3 × GI 50 , but had little impact on the level of total RNAP II (Figure 4C). The same holds true when the exposure to each compound was prolonged to 24 hours; at concentrations of 3 × GI 50 , neither phosphorylated RNAP II-Ser2 nor -Ser5 were detected for both 9 q and 9 v. As expected, the expression of MCL-1, an anti-apoptotic protein as well as one of the downstream targets of CDK9, was largely suppressed at low concentrations and completely abolished at high concentrations.…”

Section: Cellular Mechanism Of Actionmentioning

confidence: 99%

“…[7] The Cterminal domain (CTD) of RNAP II contains 52 tandemly repeated heptapeptides (i. e., Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7); phosphorylation of Ser5 residues by CDK7 contributes to initiation of transcription. [8] Furthermore, CDK7 serves as a CDKactivating kinase by means of phosphorylating CDKs 1, 2, 4 and 6; such phosphorylation regulates progression of the cell cycle. [9] Aberrant overexpression of CDK7 has been found in a wide range of cancer types.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Inhibitors of Cyclin‐Dependent Kinases 7 and 9: Design, Synthesis, Structure‐Activity Relationship Analysis and Biological Evaluation

Chen

Hassankhani

et al. 2022

ChemMedChem

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Cyclin‐dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small‐molecule inhibitors of both CDKs are highly sought‐after. Capitalising on our previous discovery of CDKI‐73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N‐pyridinylpyrimidin‐2‐amines were rationally designed, chemically synthesised and biologically assessed. Among them, N‐(6‐(4‐cyclopentylpiperazin‐1‐yl)pyridin‐3‐yl)‐4‐(imidazo[1,2‐a]pyrimidin‐3‐yl)pyrimidin‐2‐amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti‐proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4‐11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub‐G1 phase and induced apoptosis.

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“…[8][9][10] Therefore, plenty of research is ongoing for the discovery of potent and selective BRD4 inhibitors. [11,12] Since the first BRD4 inhibitor JQ-1 was developed in 2010, numerous BRD4 inhibitors have been discovered in the past 5 years, [13] and several of them have entered into clinical trials, including GSK525762 (I-BET762), OTX-015, and CPI-0610 and so on, [7,14] nevertheless, none of them is applied in clinics, and current BRD4 inhibitors are limited by their potency or bioavailability. [15] As a benzyl isoquinoline alkaloid, sanguinarine is the main active ingredient of a number of medicinal plant families like Papaveraceae, Fumariaceae, Rutaceae and in particular plants like Sanguinaria canadensis, Bocconia frutescens, Chelidonium majus, and Macleaya cordata.…”

mentioning

confidence: 99%

Sanguinarine targets BRD4 to suppress cell proliferation and migration in clear cell renal cell carcinoma

Wen

Song

et al. 2023

J Biochem & Molecular Tox

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Sanguinarine is an alkaloid with diverse biological activities, nevertheless, whether it can target epigenetic modifiers remains unknown. In this study, sanguinarine was characterized as a strong BRD4 inhibitor with IC50 = 361.3 nM against BRD4 (BD1) and IC50 = 302.7 nM against BRD4 (BD2) that can inactivate BRD4 reversibly. Additional cellular assays suggested that sanguinarine can bind BRD4 in human clear cell renal cell carcinoma (ccRCC) cell line 786‐O and inhibit cell growth with IC50 (24 h) = 0.6752 μM and IC50 (48 h) = 0.5959 μM in a BRD4 dependent manner partially. Meanwhile, sanguinarine can inhibit the migration of 786‐O cells in vitro and in vivo, and reverse epithelial−mesenchymal transition. Moreover, it can inhibit 786‐O cells proliferation in vivo in a BRD4 dependent manner partially. In sum, our study identified BRD4 as a new target of sanguinarine, and sanguinarine may serve as a potential therapeutic agent against ccRCC.

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A review on kinases phosphorylating the carboxyl-terminal domain of RNA polymerase II—Biological functions and inhibitors

Cited by 7 publications

References 158 publications

Polo-like kinase 1 promotes pulmonary hypertension

Polo-like kinase 1 promotes pulmonary hypertension

Discovery of Potent Inhibitors of Cyclin‐Dependent Kinases 7 and 9: Design, Synthesis, Structure‐Activity Relationship Analysis and Biological Evaluation

Sanguinarine targets BRD4 to suppress cell proliferation and migration in clear cell renal cell carcinoma

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