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In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones.

ABSTRACT: Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2'-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC₅₀ = 9.57 and 18.10 μM) and HEL (IC₅₀ = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.

SUBMITTER: Sanachai K

PROVIDER: S-EPMC9866339 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones.

Sanachai Kamonpan K Mahalapbutr Panupong P Tabtimmai Lueacha L Seetaha Supaphorn S Kaekratoke Nantawat N Chamni Supakarn S Azam Syed Sikander SS Choowongkomon Kiattawee K Rungrotmongkol Thanyada T

Molecules (Basel, Switzerland) 20230106 2

Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2'-methyl napabucasin exhibited potent cell growth inhibition in TF1 ( ...[more]

PMID: 36677654

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Project description:ObjectiveTo evaluate the methodological, reporting and evidence quality of systematic reviews or meta-analyses of Janus kinases (JAK) inhibitors for the treatment of rheumatoid arthritis (RA).MethodsOur study systematically retrieved reviews from various databases, spanning from inception to June 2024. Two evaluators independently assessed the methodological, reporting, and evidence quality of each review using the AMSTAR-2 and PRIAMA2020 tools. The evidence quality was evaluated according to GRADE criteria. Six aspects were evaluated: publication year, study type, homogeneity, risk of publication bias, AMSTAR-2 methodology, and PRIAMA2020 reporting quality. Excel 2016 facilitated conversion of scores into radar plots.ResultsFollowing stringent selection criteria, a total of 18 relevant studies were identified. The AMSTAR-2 scores ranged from 4 to 13 points, with five studies rated as low quality and the remaining 13 as critically low quality. All studies encompassed populations, interventions, controls, and outcome measures, demonstrating commendable integrity. However, there is room for improvement in study protocol development and registration, comprehensive search strategies, inclusion and exclusion criteria, conflict of interest disclosure, and discussion of heterogeneity. PRIAMA2020 assessments ranged from 14.5 to 21 points, with two studies scoring below 15 points due to increased bias risk from data transformation and sensitivity analysis. Notably, all reviews (100%) adhered to PRIAMA2020 guidelines for certain items but none met all criteria. GRADE evaluation included 446 outcome measures, with 158 of moderate, 156 of low, and 132 of very low quality, indicating JAK inhibitors is effective in improving RA. According to radar chart, the average rank score was 13.13. One study achieved a balanced score across all dimensions, while 11 exceeded the average, five showed significant differences in PRIAMA2020 scores, and four in AMSTAR two scores.ConclusionDespite summarizing the efficacy and safety of JAK inhibitors in treating RA, the included studies exhibited poor methodological and reporting quality, along with low-quality evidence overall. Therefore, caution is warranted among decision-makers regarding the use of JAK inhibitors in RA treatment. Urgent requirements include high-quality, multicenter studies investigating JAK inhibitors for RA.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier 413415.

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In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones.

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In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones.

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