Discovery of a potent p38α/MAPK14 kinase inhibitor: Synthesis, in vitro/in vivo biological evaluation, and docking studies

El–Gamal, Mohammed I.; Anbar, Hanan S.; Tarazi, Hamadeh; Oh, Chang‐Hyun

doi:10.1016/j.ejmech.2019.111684

Cited by 10 publications

(11 citation statements)

References 34 publications

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“…Further, it was shown that compound 12 inhibits production of TNF-α in LPS-induced THP-1 cells with IC 50 value of 58 nM. The in vivo anti-inflammatory effect of compound 12 was comparable to the effects of diclofenac with no ulcerogenic side effect on stomach 27 .…”

Section: Recent Development In Anti-inflammatory Agentsmentioning

confidence: 91%

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Bian

Wu³

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inflammation and disease are closely related. Inflammation can induce various diseases, and diseases can promote inflammatory response, and two possibly induces each other in a bidirectional loop. Inflammation is usually treated using synthetic anti-inflammatory drugs which are associated with several adverse effects hence are not safe for long-term use. Therefore, there is need for anti-inflammatory drugs which are not only effective but also safe. Several researchers have devoted to the research and development of effective anti-inflammatory drugs with little or no side effects. In this review, we studied some small molecules with reported anti-inflammatory activities and hence potential sources of anti-inflammatory agents. The information was retrieved from relevant studies published between January 2019 and May, 2021 for review. This review study was aimed to provide relevant information towards the design and development of effective and safe anti-inflammation agents.

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Section: Recent Development In Anti-inflammatory Agentsmentioning

confidence: 91%

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Bian

Wu³

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The MAPK pathway regulators include p38, JNK, and ERK1/2, which were considered a critical modulator of the inflammatory response in the lung [ 33 ]. Increased activity of MAPK, particularly p38 MAPK, could enhance the synthesis of inflammation mediators at the transcription and translation levels, which meant p38 MAPK might be a potential target to develop chemicals to inhibit inflammatory activity [ 34 ]. Recent studies showed that the suppression of the MAPK signaling pathway could attenuate LPS-induced pathological injuries and decreased expression of cytokines in ALI [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA XIST knockdown alleviates LPS-induced acute lung injury by inactivation of XIST/miR-132-3p/MAPK14 pathway

Liu

et al. 2021

Mol Cell Biochem

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Acute lung injury (ALI) is a fatal inflammatory response syndrome. LncRNA XIST (XIST) is a lung cancer-related gene and participates in pneumonia. However, whether XIST participates in lipopolysaccharides (LPS)-induced ALI remains unclear. LPS-induced inflammation model was constructed in vitro, then cell viability, cytokines, cell apoptosis, protein, and mRNA expressions were individually detected by cell counting kit-8, enzyme-linked immunosorbent assay and flow cytometry, Western blot, and qRT-PCR. A dual-luciferase reporter assay confirmed the relationships among XIST, miR-132-3p, and MAPK14. Furthermore, inflammation and conditions after knockdown of XIST were assessed by hematoxylin and eosin staining, lung wet-to-dry weight ratio, PaO 2 /FiO 2 ratio, and malondialdehyde (MDA) contents using LPS-induced in vivo model. Our findings indicated that the LPS challenge decreased cell viability, increased cell apoptosis, and caused secretions of pro-inflammatory cytokines. Noticeably, LPS significantly upregulated XIST, MAPK14, and downregulated miR-132-3p. Mechanistically, XIST acted as a molecular sponge to suppress miR-132-3p, and MAPK14 was identified as a target of miR-132-3p. Functional analyses demonstrated that XIST silencing remarkably increased cell survival and alleviated cell death and lung injury through decreasing TNF-α, IL-1β, IL-6, accumulation of inflammatory cells, alveolar hemorrhage, MDA release, and increased PaO 2 /FiO 2 ratio, as well as upregulating Bcl-2, and downregulating Bax, MAPK14, and p-extracellular signal-regulated kinases ½. In contrast, inhibition of the miR-132-3p antagonized the effects of XIST silencing. In conclusion, inhibition of XIST exhibited a protective role in LPS-induced ALI through modulating the miR-132-3p/MAPK14 axis.

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“…P38α/MAPK1’s role in inflammatory diseases is the control and management of the production of cytokines (tumornecrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-1b (IL-1b)), thus regulating the downstream signaling that mediates inflammatory response. Inflammatory disorders such as rheumatoid arthritis, inflammatory bowel syndrome, and psoriasis can be managed with p38α /MAPK1 inhibition [ 69 ].…”

Section: Pyrazole-based P38α/mapk14 Kinase Inhibitorsmentioning

confidence: 99%

“…The phenol was designed as hydroxyl or methoxy derivatives, investigating the hydrophobicity as well as the potential of H-bonding. The N -phenyl arm was attached to the halogenated phenyl ring tethered with urea or amide linkers, testing the effect of the length of the tether as well as the possibility of extra H-bonding due to the additional NH group in the urea tether compared to amide [ 69 ].…”

Section: Pyrazole-based P38α/mapk14 Kinase Inhibitorsmentioning

confidence: 99%

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

et al. 2022

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Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011–2020).

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Discovery of a potent p38α/MAPK14 kinase inhibitor: Synthesis, in vitro/in vivo biological evaluation, and docking studies

Cited by 10 publications

References 34 publications

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

LncRNA XIST knockdown alleviates LPS-induced acute lung injury by inactivation of XIST/miR-132-3p/MAPK14 pathway

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

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