scholarly journals Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 176 ◽  
Author(s):  
Andrew Paul ◽  
Joanne Edwards ◽  
Christopher Pepper ◽  
Simon Mackay
Keyword(s):  
Drug Targets ◽  
Kinase Inhibitors ◽  
Nuclear Factor Κb ◽  
Tumour Microenvironment ◽  
Pharmacological Intervention ◽  
Cancer Drug ◽  
Nuclear Factor ◽  
Transcriptional Responses ◽  
Cancer Hallmarks ◽  
Mutational Status

The cellular kinases inhibitory-κB kinase (IKK) α and Nuclear Factor-κB (NF-κB)-inducing kinase (NIK) are well recognised as key central regulators and drivers of the non-canonical NF-κB cascade and as such dictate the initiation and development of defined transcriptional responses associated with the liberation of p52-RelB and p52-p52 NF-κB dimer complexes. Whilst these kinases and downstream NF-κB complexes transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes, they also play a key role in the pathogenesis of a number of inflammatory-based conditions and diverse cancer types, which for the latter may be a result of background mutational status. IKKα and NIK, therefore, represent attractive targets for pharmacological intervention. Here, specifically in the cancer setting, we reflect on the potential pathophysiological role(s) of each of these kinases, their associated downstream signalling outcomes and the stimulatory and mutational mechanisms leading to their increased activation. We also consider the downstream coordination of transcriptional events and phenotypic outcomes illustrative of key cancer ‘Hallmarks’ that are now increasingly perceived to be due to the coordinated recruitment of both NF-κB-dependent as well as NF-κB–independent signalling. Furthermore, as these kinases regulate the transition from hormone-dependent to hormone-independent growth in defined tumour subsets, potential tumour reactivation and major cytokine and chemokine species that may have significant bearing upon tumour-stromal communication and tumour microenvironment it reiterates their potential to be drug targets. Therefore, with the emergence of small molecule kinase inhibitors targeting each of these kinases, we consider medicinal chemistry efforts to date and those evolving that may contribute to the development of viable pharmacological intervention strategies to target a variety of tumour types.

scholarly journals Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases

Science ◽  
2019 ◽  
Vol 366 (6461) ◽  
pp. 109-115 ◽  
Author(s):  
Yasushi Kondo ◽  
Jana Ognjenović ◽  
Saikat Banerjee ◽  
Deepti Karandur ◽  
Alan Merk ◽  
...  
Keyword(s):  
Drug Targets ◽  
Active Sites ◽  
Kinase Inhibitors ◽  
Distal Segment ◽  
Kinase Domain ◽  
Terminal Segment ◽  
Cancer Drug ◽  
Active Conformation ◽  
Raf Kinase ◽  
Cryo Electron Microscopy

Raf kinases are important cancer drug targets. Paradoxically, many B-Raf inhibitors induce the activation of Raf kinases. Cryo–electron microscopy structural analysis of a phosphorylated B-Raf kinase domain dimer in complex with dimeric 14-3-3, at a resolution of ~3.9 angstroms, shows an asymmetric arrangement in which one kinase is in a canonical “active” conformation. The distal segment of the C-terminal tail of this kinase interacts with, and blocks, the active site of the cognate kinase in this asymmetric arrangement. Deletion of the C-terminal segment reduces Raf activity. The unexpected asymmetric quaternary architecture illustrates how the paradoxical activation of Raf by kinase inhibitors reflects an innate mechanism, with 14-3-3 facilitating inhibition of one kinase while maintaining activity of the other. Conformational modulation of these contacts may provide new opportunities for Raf inhibitor development.

scholarly journals Two Waves of Nuclear Factor κb Recruitment to Target Promoters

2001 ◽  
Vol 193 (12) ◽  
pp. 1351-1360 ◽  
Author(s):  
Simona Saccani ◽  
Serafino Pantano ◽  
Gioacchino Natoli
Keyword(s):  
Adhesion Molecules ◽  
Inflammatory Cytokines ◽  
Chromatin Structure ◽  
Chromatin Immunoprecipitation ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Transcriptional Responses ◽  
Cytokines And Chemokines ◽  
Target Promoters

Proinflammatory stimuli induce the rapid and transient translocation of nuclear factor (NF)-κB to the nucleus, where it activates transcription from several genes, including those encoding inflammatory cytokines and chemokines, adhesion molecules, and cytoprotective proteins. Using chromatin immunoprecipitation, we show that after an acute stimulation two distinct waves of NF-κB recruitment to target promoters occur: a fast recruitment to constitutively and immediately accessible (CIA) promoters and a late recruitment to promoters requiring stimulus-dependent modifications in chromatin structure to make NF-κB sites accessible (promoters with regulated and late accessibility [RLA]). Our results suggest that a mechanism of specificity in NF-κB–dependent transcriptional responses relies on the ability of individual stimuli to make RLA promoters accessible to NF-κB before its rapid extrusion from the nucleus.

scholarly journals RANK–RANKL signalling in cancer

2016 ◽  
Vol 36 (4) ◽  
Author(s):  
Nathalie Renema ◽  
Benjamin Navet ◽  
Marie-Françoise Heymann ◽  
Frédéric Lezot ◽  
Dominique Heymann
Keyword(s):  
Cancer Cells ◽  
Cell Types ◽  
Nuclear Factor Κb ◽  
Tumour Microenvironment ◽  
Cancer Development ◽  
Specific Cell ◽  
Nuclear Factor ◽  
Pulmonary Epithelium ◽  
Extracellular Matrix Components ◽  
Receptor Activator

Oncogenic events combined with a favourable environment are the two main factors in the oncological process. The tumour microenvironment is composed of a complex, interconnected network of protagonists, including soluble factors such as cytokines, extracellular matrix components, interacting with fibroblasts, endothelial cells, immune cells and various specific cell types depending on the location of the cancer cells (e.g. pulmonary epithelium, osteoblasts). This diversity defines specific “niches” (e.g. vascular, immune, bone niches) involved in tumour growth and the metastatic process. These actors communicate together by direct intercellular communications and/or in an autocrine/paracrine/endocrine manner involving cytokines and growth factors. Among these glycoproteins, RANKL (receptor activator nuclear factor-κB ligand) and its receptor RANK (receptor activator nuclear factor), members of the TNF and TNFR superfamilies, have stimulated the interest of the scientific community. RANK is frequently expressed by cancer cells in contrast with RANKL which is frequently detected in the tumour microenvironment and together they participate in every step in cancer development. Their activities are markedly regulated by osteoprotegerin (OPG, a soluble decoy receptor) and its ligands, and by LGR4, a membrane receptor able to bind RANKL. The aim of the present review is to provide an overview of the functional implication of the RANK/RANKL system in cancer development, and to underline the most recent clinical studies.

Novel IκB kinase inhibitors for treatment of nuclear factor-κB-related diseases

2011 ◽  
Vol 20 (3) ◽  
pp. 395-405 ◽  
Author(s):  
Jun-Ichi Suzuki ◽  
Masahito Ogawa ◽  
Susumu Muto ◽  
Akiko Itai ◽  
Mitsuaki Isobe ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Iκb Kinase

scholarly journals TARGETING NUCLEAR FACTOR KAPPA B WITH CHELATED ZINC COMPOUNDS TOWARDS ANTICANCER DRUG DESIGN

2021 ◽  
pp. 123-127
Author(s):  
NAGALAKSHMI K. ◽  
SHILA S. ◽  
INBATHAMIZH L. ◽  
THENMOZHI A. ◽  
RASAPPAN P. ◽  
...  
Keyword(s):  
Drug Design ◽  
Anticancer Drug ◽  
Minimum Energy ◽  
Data Bank ◽  
Nuclear Factor Κb ◽  
Dimensional Structure ◽  
Cancer Drug ◽  
Nuclear Factor ◽  
Zinc Compounds ◽  
Lipinski’S Rule

Objective: The objective of the study was to analyse the target-ligand interactions between nuclear factor-κB (NF-κB) and chelated Zinc compounds and to explore the anticancer drug potential of these ligands by a bio computational approach. Methods: Bioinformatics databases and tools were applied for the study. Three dimensional structure of the target NF-κB was retrieved from Protein Data Bank (PDB). The optimized structures of two chelated Zinc compounds, Zinc acetate and Zinc orotate were taken for docking studies with the target using docking tool AutoDock 4.2. Drug properties of the ligands were further assessed by Molinspiration server. Results: Docking results as predicted by AutoDock and as visualized by PyMol viewer were effective for both the ligands. Comparatively, Zinc orotate showed minimum energy and more interactions with the target. Both the ligands satisfied the Lipinski’s rule of five with zero violations. Conclusion: The findings emphasized the promising role of chelated Zinc compounds as potent drug candidates in anti-cancer drug design against NF-κB.

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