Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders

Farag, Ahmed Karam; Elkamhawy, Ahmed; Londhe, Ashwini M.; Lee, Kyung‐Tae; Pae, Ae Nim; Roh, Eun Joo

doi:10.1016/j.ejmech.2017.10.003

Cited by 30 publications

(25 citation statements)

References 41 publications

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“…Modification in the activity and expression of LCK is linked to several diseases, including asthma, cancer, diabetes, psoriasis, atherosclerosis, inflammatory bowel disease, and RA [30]. Farag et al [31] showed that potent and selective LCK inhibitors could be used in inflammatory diseases, including RA. These findings suggest that the LCK downregulation might reduce inflammation in rheumatoid synovium.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis

Xiong

Liu

et al. 2019

Med Sci Monit

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Background Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. Material/Methods Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Results DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. Conclusions The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis

Xiong

Liu

et al. 2019

Med Sci Monit

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“…In glial cells, compound 1 inhibited iNOS and consequently the production of NO in a dose‐dependent manner, thus inhibiting the release of several inflammatory mediators without affecting cyclooxygenase‐2 or apolipoprotein E levels. Additionally, it decreased neuronal loss, and diminished amyloid plaque deposition in vivo proving that inhibition of inflammatory mediators in the hippocampus can reduce neuronal loss …”

Section: Dapks Inhibitorsmentioning

confidence: 96%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

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“…In the framework of the systemic study of the effect of different constituents in the aromatic moiety on the antinociceptive potency of lappaconitine, we synthesized pyrimidine-containing lappaconitine derivatives and evaluated their analgesic activity in vivo by standard experimental pain models. Aryl substituted pyrimidines are considered as important pharmacophores possessing a wide diversity of valuable biological properties, including analgesic activity [27][28][29][30][31]. This scaffold was found to be a ubiquitous motif in many biologically active compounds and around these, a variety of novel drug candidates with excellent pharmaceutical profile can be designed.…”

Section: Introductionmentioning

confidence: 99%

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

et al. 2020

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Convenient and efficient routes to construct hybrid molecules containing diterpene alkaloid lappaconitine and pyrimidine fragments are reported. One route takes place via first converting of lappaconitine to 1-ethynyl-lappaconitine, followed by the Sonogashira cross-coupling-cyclocondensation sequences. The other involves the palladium-catalyzed carbonylative Sonogashira reaction of 5′-iodolappaconitine with aryl acetylene and Mo (CO)6 as the CO source in acetonitrile and subsequent cyclocondensation reaction of the generated alkynone with amidines. The reaction proceeded cleanly in the presence of the PdCl2-(1-Ad)2PBn∙HBr catalytic system. The protocol provides mild reaction conditions, high yields, and high atom and step-economy. Pharmacological screening of lappaconitine-pyrimidine hybrids for antinociceptive activity in vivo revealed that these compounds possessed high activity in experimental pain models, which was dependent on the nature of the substituent in the 2 and 6 positions of the pyrimidine nucleus. Docking studies were undertaken to gain insight into the possible binding mode of these compounds with the voltage-gated sodium channel 1.7. The moderate toxicity of the leading compound 12 (50% lethal dose (LD50) value was more than 600 mg/kg in vivo) and cytotoxicity to cancer cell lines in vitro encouraged the further design of therapeutically relevant analogues based on this novel type of lappaconitine–pyrimidine hybrids.

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Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders

Cited by 30 publications

References 41 publications

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

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