Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

He, Libang; Pei, Heying; Lan, Tingxuan; Tang, Minghai; Zhang, Chufeng; Chen, Lijuan

doi:10.1002/ardp.201700194

Cited by 18 publications

(21 citation statements)

References 26 publications

(36 reference statements)

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“…Based on the unique cysteine 909 residue (Cys909) of JAK-3 at the gatekeeper position, He et al integrated a new irreversible covalent inhibitor III-4 which is highly potent and selective in targeting JAK-3. [168] III-4 has inhibitory effect on JAK-3 and good antirheumatic effect, suggesting that III-4 possesses a potential to be an efficacious treatment for RA. Wei and coworkers synthesized a prodrug of Tofacitinib (P-Tofa) which enhanced Tofa's therapeutic efficacy by conjugating the drug to N-HPMA copolymer via an acid cleavable carbamate linker.…”

Section: Jak/stat Pathways Inhibitors Therapymentioning

confidence: 99%

“…Based on the unique cysteine 909 residue (Cys909) of JAK‐3 at the gatekeeper position, He et al integrated a new irreversible covalent inhibitor III‐4 which is highly potent and selective in targeting JAK‐3 168. III‐4 has inhibitory effect on JAK‐3 and good antirheumatic effect, suggesting that III‐4 possesses a potential to be an efficacious treatment for RA.…”

Section: Nanotherapeutics Of Ra Based On Nanodrugsmentioning

confidence: 99%

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Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

Wang

Meng

et al. 2020

Adv Healthcare Materials

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Early diagnosis, standardized treatment, and regular monitoring are the clinical treatment principle of rheumatoid arthritis (RA). The overarching principles and recommendations of treat‐to‐target (T2T) in RA advocate remission as the optimum aim, especially for patients with very early disease who are initiating therapy with anti‐RA medications. However, traditional anti‐RA drugs cannot selectively target the inflammatory areas and may cause serious side effects due to its short biological half‐life and poor bioavailability. These limitations have significantly driven the research and application of nanomaterial‐based drugs in theranostics of RA. Nanomedicines have appropriate sizes and easily modified surfaces which can enhance their biological compatibility and prolong circulation time of drug‐loading systems in vivo. Traditional T2T regimens cannot evaluate the efficacy of drugs in real time, while clinical drug nanosizing can realize the integration of diagnosis and treatment of RA. This review bridges clinically proposed T2T concepts and nanomedicine in an integrated system for RA early‐stage diagnosis and treatment. The most advanced progress in various nanodrug delivery systems for theranostics of RA is summarized, establishing a clear path and a new perspective for further optimization of T2T. Finally, the key facing challenges are discussed and prospects are addressed.

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Section: Jak/stat Pathways Inhibitors Therapymentioning

confidence: 99%

Section: Nanotherapeutics Of Ra Based On Nanodrugsmentioning

confidence: 99%

Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

Wang

Meng

et al. 2020

Adv Healthcare Materials

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“…is an important signal mediated by proinflammatory cytokines and has a potential benefit in the treatment of autoimmune disorders. 30 Hence, we selected JAK3 as the candidate gene in our study.…”

Section: Jak3 Is Significantly Increased In Synovial Tissues Of Patmentioning

confidence: 99%

MiR‐1193 represses the proliferation and induces the apoptosis of interleukin‐1β‐treated fibroblast‐like synoviocytes via targeting JAK3

Liu

Ren

2020

Int J of Rheum Dis

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Objectives: To explore the roles of miR-1193/Janus kinase 3 (JAK3) axis and the potential mechanism in rheumatoid arthritis (RA). Methods: The dysregulated genes and microRNAs (miRNAs) were screened using the datasets of GSE12021 and GSE72564, while the upstream miRNA of JAK3 was forecasted by TargetScan. Then the MH7A cells were treated with interleukin-1β (IL-1β) to induce local inflammation. Double luciferase report assay was used to estimate the association between JAK3 and miR-1193. Flow cytometry and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays were taken to analyze the apoptosis and proliferation of MH7A cells with IL-1β-induced inflammation, respectively. The relative expression of genes and proteins were detected by quantitative real-time polymerase chain reaction and western blot analyses. Finally, rescue experiments were employed to explore the effects of miR-1193/JAK3 axis on IL-1βinduced inflammation. Results: JAK3 was notably up-regulated in RA, and was targeted and negatively regulated by miR-1193 which was lowly expressed in RA tissues and IL-1β-treated cells. MiR-1193 mimic significantly inhibited while miR-1193 inhibitor promoted the proliferation of MH7A cells with IL-1β-induced inflammation. Furthermore, overexpression of JAK3 presented auxo-action while depletion of JAK3 exhibited inhibitory effect on the proliferation of MH7A cells with IL-1β-induced inflammation, which could be weakened by miR-1193 mimic and miR-1193 inhibitor, respectively. Analogously, JAK3 recovered the cell proliferation that inhibited by miR-1193 mimic and inhibited cell apoptosis enhanced by miR-1193 mimic. Conclusion: Up-regulation of miR-1193 suppressed the proliferation and expedited the apoptosis of MH7A cells with IL-1β-induced inflammation through targeting JAK3, which might provide novel understanding on the mechanism underlying RA.

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“…As the authors state, the docking procedure is also not a blind‐docking protocol, meaning that knowledge about the binding site is definitely required. With CovalentDock Cloud the method has been made available through a webserver (http://docking.sce.ntu.edu.sg/), which has already been used to suggest binding modes of new peptidomimetics with α,β‐unsaturated ketone function as inhibitors of CHIKV nsP2 protease, as well as to analyze the binding region of a selective JAK3 inhibitor …”

Section: Modeling Covalent Bond Formation In Docking Approachesmentioning

confidence: 99%

Docking of Covalent Ligands: Challenges and Approaches

Sotriffer

2018

Molecular Informatics

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Covalent ligands have recently regained considerable attention in drug discovery. The rational design of such ligands, however, is still faced with particular challenges, mostly related to the fact that covalent bond formation is a quantum mechanical phenomenon which cannot adequately be handled by the force fields or empirical approaches typically used for noncovalent protein-ligand interactions. Although the necessity for quantum chemical approaches is clear, they cannot yet routinely be applied on large data sets of ligands or for a broader exploration of binding modes in docking calculations. On the other hand, technical solutions for performing docking calculations with covalent ligands are available, but their scope is normally quite limited. Scoring functions typically neglect the contribution from covalent bond formation completely. In this situation, the question arises how to approach covalent ligands and which methods to choose for their docking and design.

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Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

Cited by 18 publications

References 26 publications

Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

MiR‐1193 represses the proliferation and induces the apoptosis of interleukin‐1β‐treated fibroblast‐like synoviocytes via targeting JAK3

Docking of Covalent Ligands: Challenges and Approaches

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