Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer

Scott, Fiona; Angela, M.; Pennicott, Lewis E.; Reuillon, Tristan; Massirer, Katlin B.; Elkins, J.M.; Ward, Simon E.

doi:10.1016/j.bmcl.2020.127040

Cited by 15 publications

(15 citation statements)

References 34 publications

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“…Several attempts to target the PRK kinase domain have been made with inhibitors that target the active site [37,52,[143][144][145][146][147][148] but, as expected, the well-documented issues with specificity around small molecule inhibitors of kinases apply equally to PRK inhibitors [149]. The complex regulation that we have described above suggests that engineering more specific inhibitors, e.g.…”

Section: Discussionmentioning

confidence: 71%

The structure and function of protein kinase C-related kinases (PRKs)

Sophocleous

Owen

Mott

2021

Biochemical Society Transactions

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The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structural description of the regulatory and catalytic domains, which facilitates the understanding of their regulation in molecular detail. We then examine their diverse physiological roles in cytoskeletal reorganization, cell adhesion, chromatin remodelling, androgen receptor signalling, cell cycle regulation, the immune response, glucose metabolism and development, highlighting isoform redundancy but also isoform specificity. Finally, we consider the involvement of PRKs in pathologies, including cancer, heart disease and bacterial infections. The abundance of PRK-driven pathologies suggests that these enzymes will be good therapeutic targets and we briefly report some of the progress to date.

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Section: Discussionmentioning

confidence: 71%

The structure and function of protein kinase C-related kinases (PRKs)

Sophocleous

Owen

Mott

2021

Biochemical Society Transactions

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“…In addition, PKN2 has been suggested to play critical roles in actin stress fibre formation in NIH3T3 cells 30 . PKN2 inhibitors are currently in development for cancer therapy 31 and the PKN2 inhibitor Fostamatinib has been suggested as a drug repurposing candidate for the treatment of acute respiratory distress syndrome in severe COVID-19 patients 32 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis

Oldham

Jenkins

Leavy

et al. 2022

Preprint

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Background: Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterised by progressive scarring of the lungs. This leads to the lungs becoming stiffer, reducing lung capacity, and impeding gas transfer. We aimed to identify genetic variants associated with either declining lung capacity or gas transfer after diagnosis of IPF. Methods: We performed a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity for lung of carbon monoxide (DLco) in individuals diagnosed with IPF from three studies. Suggestively significant variants were investigated further in an additional study. Variants were defined as significantly associated if they had a meta-analysis p<5x10-8, had consistent direction of effects across all studies and were nominally significant (p<0.05) in each study. Findings: 1,048 individuals with measures of longitudinal FVC and 729 individuals with longitudinal measures of DLco passed quality control. In total, 4,560 measures of FVC and 2,795 measures of DLco and over 7 million genetic variants were included in the analysis. One variant located in an antisense RNA gene for Protein Kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 ml/year per risk allele, 95% CI [-180, -100], p=9.14x10-12). Interpretation: These results identify a possible druggable target involved in promoting IPF disease progression. Funding: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, National Institute of Health/National Heart, Lung and Blood Institute

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“…Protein kinase N2 (PKN2) is a PKC-associated serine/ threonine-protein kinase and act as a chemical tool to explore several types of cancer [43]. e existent study of the function of PKN2 in tumor is relatively controversial.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PAX8-AS1 Inhibits Malignant Phenotypes of Papillary Thyroid Carcinoma Cells via miR-96-5p/PKN2 Axis

Zhou

et al. 2021

International Journal of Endocrinology

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Background. Thyroid carcinoma (THCA) is the most frequent endocrine malignancy. Papillary thyroid carcinoma (PTC) is the major subtype of THCA, accounting for over 80% of all THCA cases. LncRNA PAX8-AS1, a tumor suppressor associated with various human cancers, has been reported to be relevant to the regulation of all sorts of cellular processes. The purpose of this study was to verify the role of PAX8-AS1 in PTC. Methods. Three human PTC cell lines (K1, TPC-1, and IHH4) and one normal human thyroid cell line, Nthy-ori3-1, were used in our study. The expression of genes was detected by qRT-PCR. The bioinformatic analysis and luciferase reporter assay were used to confirm the binding relationship of PAX8-AS1 to miR-96-5p, and the targeting relationship of miR-96-5p to PKN2 was also predicted. Cell proliferation and apoptosis capacities were assessed by MTT and flow cytometry, respectively. EdU assay was used to detect cell proliferation. Western blot assay was employed to examine protein expression. Results. The expression of PAX8-AS1 was decreased in PTC tissues and cells. PAX8-AS1 overexpression inhibited the proliferation of PTC cells and promoted cell apoptosis. In addition, PAX8-AS1 bonds with miR-96-5p, whose downregulation elevated the expression of PKN2 in PTC cells. Importantly, according to the rescue experiments, PKN2 silencing partially reversed the inhibitory effects of PAX8-AS1 expression on PTC cell proliferation and apoptosis. Conclusions. We found that the PAX8-AS1/miR-96-5p/PKN2 axis was closely related to the progression of PTC, which could be a potential target for treating PTC patients.

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Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer

Cited by 15 publications

References 34 publications

The structure and function of protein kinase C-related kinases (PRKs)

The structure and function of protein kinase C-related kinases (PRKs)

Genome-wide analysis of longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis

Overexpression of PAX8-AS1 Inhibits Malignant Phenotypes of Papillary Thyroid Carcinoma Cells via miR-96-5p/PKN2 Axis

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