Ligand–Protein Interactions of Selective Casein Kinase 1δ Inhibitors

Mente, Scot; Arnold, Eric P.; Butler, Todd W.; Subramanyam, Chakrapani; Chandrasekaran, Ramalakshmi Y.; Cherry, Kevin; DiRico, Ken; Doran, Angela C.; Fisher, Katherine; Galatsis, Paul; Green, Michael; Hayward, Matthew M.; Humphrey, John M.; Knafels, John D.; Li, Jianke; Liu, Shenping; Marconi, Michael; McDonald, Scott; Ohren, Jeffrey F.; Paradis, Vanessa; Sneed, Blossom; Walton, Kenneth G.; Wager, Travis T.

doi:10.1021/jm4006324

Cited by 27 publications

(27 citation statements)

References 29 publications

(78 reference statements)

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“…Furthermore, core catalytic residues Lys38 and Asp149 [ 13 , 31 ] coordinate a structural water within the catalytic cleft which donates another hydrogen bond towards an imidazole nitrogen of the respective inhibitor. Gatekeeper residue Met82 is rotated by 180° towards Pro66 [ 13 , 31 ], thereby permitting access to the hydrophobic pocket I ( selectivity pocket , HPI ) [ 2 , 34 ] which is ideally occupied by the 4-fluorophenyl moiety [ 31 , 35 ]. Molecular modeling further suggests five-membered heterocycles to dictate an ideal angle for positioning of the vicinal aryl moieties within the ATP-binding pocket of CK1δ [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

et al. 2017

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The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50 CK1δ = 4 nM, IC50 CK1ε = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ε = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 µM) and Panc89 (EC50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α.

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Section: Resultsmentioning

confidence: 99%

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

et al. 2017

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“…CK1δ was modelled from the 3D crystallographic structure corresponding to the entry 4KBK that contains the crystallographic ligand 1QG. Only chain B, since it is naturally a monomer, was considered for further studies [ 64 ]. DYRK1A was modelled from the crystal 3D structure with a PDB ID 4AZE that contains the crystallographic ligand 3RA.…”

Section: Methodsmentioning

confidence: 99%

“…It was carried out through a bibliographical search plus a database analysis. The bibliographical search was conducted using several studies in which inhibitors against the selected kinases were identified describing each compound binding mode [ 25 , 31 , 32 , 50 , 51 , 52 , 64 , 81 , 82 ]. The database search was done using an in-house, recently constructed database.…”

Section: Methodsmentioning

confidence: 99%

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

Llorach-Parés

Nonell-Canals²,

Sánchez-Martínez³

et al. 2017

Marine Drugs

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Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A–G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer’s disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

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“…AD is not an exception, and several drug candidates have been developed from natural sources against the different therapeutic targets identified to date [ 21 , 22 , 23 ]. In fact, few reasonable selective and potent GSK3β, CK1δ, DYRK1A, and CLK1 inhibitors have been described so far, most of them being marine natural products or derived molecules from them [ 5 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer’s Disease: A Computational Study

Llorach-Parés

Nonell-Canals²,

Ávila

et al. 2018

Marine Drugs

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Alzheimer’s disease (AD) is becoming one of the most disturbing health and socioeconomic problems nowadays, as it is a neurodegenerative pathology with no treatment, which is expected to grow further due to population ageing. Actual treatments for AD produce only a modest amelioration of symptoms, although there is a constant ongoing research of new therapeutic strategies oriented to improve the amelioration of the symptoms, and even to completely cure the disease. A principal feature of AD is the presence of neurofibrillary tangles (NFT) induced by the aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Glycogen synthetase kinase-3 beta (GSK3β), casein kinase 1 delta (CK1δ), dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and dual-specificity kinase cdc2-like kinase 1 (CLK1) have been identified as the principal proteins involved in this process. Due to this, the inhibition of these kinases has been proposed as a plausible therapeutic strategy to fight AD. In this study, we tested in silico the inhibitory activity of different marine natural compounds, as well as newly-designed molecules from some of them, over the mentioned protein kinases, finding some new possible inhibitors with potential therapeutic application.

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Ligand–Protein Interactions of Selective Casein Kinase 1δ Inhibitors

Cited by 27 publications

References 29 publications

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer’s Disease: A Computational Study

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