Anwulignan is a novel JAK1 inhibitor that suppresses non‐small cell lung cancer growth

Xie, Xiaodong; Wang, Xiangyu; Shi, Xiaodan; Zhang, Yuanyuan; Laster, Kyle Vaughn; Liu, Kangdong; Dong, Zigang; Kim, Dong Joon

doi:10.1111/jcmm.16289

Cited by 9 publications

(5 citation statements)

References 41 publications

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“…In lung adenocarcinoma patients, the overall survival time was substantially reduced in patients with EGFR-amplified tumors expressing greater levels of phosphorylated JAK1 compared with individuals with tumors without one or both of these traits. Additionally, JAK inhibition was demonstrated to limit the development of human lung adenocarcinoma with a K-RAS mutation ( Xie et al, 2021 ). AML and breast cancer patients have exhibited several STAT5-activating JAK1 mutations ( Hornakova et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Potent and Selective JAK1 Lead Compounds Through Ligand-Based Drug Design Approaches

et al. 2022

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JAK1 plays a significant role in the intracellular signaling by interacting with cytokine receptors in different types of cells and is linked to the pathogenesis of various cancers and in the pathology of the immune system. In this study, ligand-based pharmacophore modeling combined with virtual screening and molecular docking methods was incorporated to identify the potent and selective lead compounds for JAK1. Initially, the ligand-based pharmacophore models were generated using a set of 52 JAK1 inhibitors named C-2 methyl/hydroxyethyl imidazopyrrolopyridines derivatives. Twenty-seven pharmacophore models with five and six pharmacophore features were generated and validated using potency and selectivity validation methods. During potency validation, the Guner-Henry score was calculated to check the accuracy of the generated models, whereas in selectivity validation, the pharmacophore models that are capable of identifying selective JAK1 inhibitors were evaluated. Based on the validation results, the best pharmacophore models ADHRRR, DDHRRR, DDRRR, DPRRR, DHRRR, ADRRR, DDHRR, and ADPRR were selected and taken for virtual screening against the Maybridge, Asinex, Chemdiv, Enamine, Lifechemicals, and Zinc database to identify the new molecules with novel scaffold that can bind to JAK1. A total of 4,265 hits were identified from screening and checked for acceptable drug-like properties. A total of 2,856 hits were selected after ADME predictions and taken for Glide molecular docking to assess the accurate binding modes of the lead candidates. Ninety molecules were shortlisted based on binding energy and H-bond interactions with the important residues of JAK1. The docking results were authenticated by calculating binding free energy for protein–ligand complexes using the MM-GBSA calculation and induced fit docking methods. Subsequently, the cross-docking approach was carried out to recognize the selective JAK1 lead compounds. Finally, top five lead compounds that were potent and selective against JAK1 were selected and validated using molecular dynamics simulation. Besides, the density functional theory study was also carried out for the selected leads. Through various computational studies, we observed good potency and selectivity of these lead compounds when compared with the drug ruxolitinib. Compounds such as T5923555 and T5923531 were found to be the best and can be further validated using in vitro and in vivo methods.

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Section: Introductionmentioning

confidence: 99%

Identification of Potent and Selective JAK1 Lead Compounds Through Ligand-Based Drug Design Approaches

et al. 2022

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“…Disrupting the interaction between RAS and PI3-kinase diminishes the growth and survival of EGFR-mutant lung cancer cells [ 35 ]. Furthermore, the inhibition of JAK1 with Anwulignan effectively suppresses the growth of non-small cell lung cancer by targeting the JAK1/STAT3 signaling pathway [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Green Seaweed Caulerpa racemosa as a Novel Non-Small Cell Lung Cancer Inhibitor in Overcoming Tyrosine Kinase Inhibitor Resistance: An Analysis Employing Network Pharmacology, Molecular Docking, and In Vitro Research

Lau,

Nurkolis,

Park

et al. 2024

Marine Drugs

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The marine environment provides a rich source of distinct creatures containing potentially revolutionary bioactive chemicals. One of these organisms is Caulerpa racemosa, a type of green algae known as green seaweed, seagrapes, or green caviar. This organism stands out because it has great promise for use in medicine, especially in the study of cancer. Through the utilization of computational modeling (in silico) and cellular laboratory experiments (in vitro), the chemical components included in the green seaweed C. racemosa were effectively analyzed, uncovering its capability to treat non-small cell lung cancer (NSCLC). The study specifically emphasized blocking SRC, STAT3, PIK3CA, MAPK1, EGFR, and JAK1 using molecular docking and in vitro. These proteins play a crucial role in the EGFR Tyrosine Kinase Inhibitor Resistance pathway in NSCLC. The chemical Caulersin (C2) included in C. racemosa extract (CRE) has been identified as a potent and effective agent in fighting against non-small cell lung cancer (NSCLC), both in silico and in vitro. CRE and C2 showed a level of inhibition similar to that of osimertinib (positive control/NSCLC drug).

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“…Several bioactive compounds, such as gomisin N, gomisin A, gomisin J, anwulignan, and α-iso-cubebenol have been identified in S. chinensis [ 16 , 20 , 24 , 25 , 26 ], and these observations attracted considerable research attention because of the therapeutic potentials of these compounds. In the present study, we investigated the molecular mechanisms responsible for the anti-cancer effects of α-cubebenoate in CT26 cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effects of α-Cubebenoate Derived from Schisandra chinensis in CT26 Colon Cancer Cells

et al. 2022

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α-Cubebenoate derived from Schisandra chinensis has been reported to possess anti-allergic, anti-obesity, and anti-inflammatory effects and to exhibit anti-septic activity, but its anti-cancer effects have not been investigated. To examine the anti-cancer activity of α-cubebenoate, we investigated its effects on the proliferation, apoptosis, and metastasis of CT26 cells. The viabilities of CT26 cells (a murine colorectal carcinoma cell line) and HCT116 cells (a human colon cancer cell line) were remarkably and dose-dependently diminished by α-cubebenoate, whereas the viability of CCD-18Co cells (a normal human fibroblast cell line) were unaffected. Furthermore, α-cubebenoate treatment increased the number of apoptotic CT26 cells as compared with Vehicle-treated cells and increased Bax, Bcl-2, Cas-3, and Cleaved Cas-3 protein levels by activating the MAP kinase signaling pathway. α-Cubebenoate also suppressed CT26 migration by regulating the PI3K/AKT signaling pathway. Furthermore, similar reductions were observed in the expression levels of some migration-related proteins including VEGFA, MMP2, and MMP9. Furthermore, reduced VEGFA expression was found to be accompanied by the phosphorylations of FAK and MLC in the downstream signaling pathway of adhesion protein. The results of the present study provide novel evidence that α-cubebenoate can stimulate apoptosis and inhibit metastasis by regulating the MAPK, PI3K/AKT, and FAK/MLC signaling pathways.

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Anwulignan is a novel JAK1 inhibitor that suppresses non‐small cell lung cancer growth

Cited by 9 publications

References 41 publications

Identification of Potent and Selective JAK1 Lead Compounds Through Ligand-Based Drug Design Approaches

Identification of Potent and Selective JAK1 Lead Compounds Through Ligand-Based Drug Design Approaches

Green Seaweed Caulerpa racemosa as a Novel Non-Small Cell Lung Cancer Inhibitor in Overcoming Tyrosine Kinase Inhibitor Resistance: An Analysis Employing Network Pharmacology, Molecular Docking, and In Vitro Research

Anti-Cancer Effects of α-Cubebenoate Derived from Schisandra chinensis in CT26 Colon Cancer Cells

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