Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

Wang, Wanqi; Diao, Yanyan; Li, Wenjie; Luo, Yating; Yang, Tingyuan; Zhao, Yanfang; Qi, Tiantian; Xu, Fangling; Ma, Xiangyu; Ge, Huan; Liang, Ying-Fan; Zhao, Zhenjiang; Liang, Xin; Wang, Rui; Zhu, Lili; Li, Honglin; Xu, Yufang

doi:10.1016/j.bmcl.2019.04.011

Cited by 12 publications

(3 citation statements)

References 38 publications

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Section: Resultsmentioning

confidence: 72%

“…Our results suggested that JAK1, JAK2, and JAK3 might be important targets and play vital roles in the inhibition of LO2 and AGS cell proliferation ( Shi et al, 2019 ; Wang et al, 2019 ). In addition, amino acid residues, such as Leu855 in JAK2 ( Wang et al, 2019 ), Asp1021 in JAK1 ( Kim et al, 2015 ), and Leu828 in JAK3 ( Yu et al, 2019 ), were the common binding sites of JAKs active pocket, and docking simulations were conducted in the ATP binding sites of JAKs. Different from compounds with polar moieties to exhibit three-dimension configuration, higher docking energy and more interaction sites with JAKs ( Yu et al, 2019 ; Ren et al, 2020 ), such as Cerdulatinib used in this study, the structures of alkaloids from QAs seemed to have more rigidity, less polarity, and more hydrophobicity.…”

Section: Resultsmentioning

confidence: 72%

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Inhibitors Targeting Multiple Janus Kinases From Zanthoxylum simulans Mediate Inhibition and Apoptosis Against Gastric Cancer Cells via the Estrogen Pathway

et al. 2022

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Janus kinases (JAKs) play a key role in subtly regulating proliferation, apoptosis, and differentiation of cancer cells, and their inhibitors are actively sought as new drug leads. By developing JAKs based affinity ultrafiltration method coupled with LC/Q-TOF-MS in order to discover selective JAKs inhibitors from total quaternary alkaloids (QAs) from Zanthoxylum simulans, peak 19 (Berberine) and peak 21 (Chelerythrine) were revealed to exhibit notable selectivity on JAK1, JAK2, and JAK3 over Tyk2. In addition, Chelerythrine showed stronger inhibitory activity than the positive control (Cerdulatinib) on gastric cancer cells (AGS), while Berberine, with weaker inhibition. Chelerythrine and Berberine also showed obvious inhibition on human hepatocyte cells (LO2). Furthermore, molecular docking analysis revealed their discrepancies due to different interaction bonds and characteristic residues. Quaternary N was proposed as the functional group to enhance the selectivity of JAK1, and some specific moieties towards Asp1021, Leu855, and Leu828 were suggested to increase the selectivity for JAK1, JAK2, and JAK3, respectively. As the most potential inhibitor of JAKs from QAs, Chelerythrine exhibited distinct suppression of adhesion, migration, invasion, and stimulating apoptosis of AGS cells, which was consistent with the significant down-regulation of estrogen receptors (ER-α36, ER-α66, and ER-β1) and Src expression. In conclusion, an efficient screening approach was developed to identify Berberine and Chelerythrine as potential selective candidates from Zanthoxylum simulans with significant anti-proliferative activity against gastric carcinoma. As we know, it was the first report to propose an estrogen signal pathway for Chelerythrine in anti-gastric cancer cells (AGS) study. The results supported Chelerythrine inhibitory effects on AGS by not only direct inhibiting JAKs but also down-regulating the estrogen pathway.

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 72%

Inhibitors Targeting Multiple Janus Kinases From Zanthoxylum simulans Mediate Inhibition and Apoptosis Against Gastric Cancer Cells via the Estrogen Pathway

et al. 2022

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“…Recombinant JAK1, JAK2 and JAK3 were expressed and purified according to the published literature . JAK1, JAK2 and JAK3 kinase activity assays were performed using the Z’‐LYTE TM Kinase Assay Kit‐Tyr 6 Peptide . In these assays, fedratinib was used as the positive control, and at least three parallel experiments were performed.…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

Wang

et al. 2019

Chin. J. Chem.

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Summary of main observation and conclusion Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects, but the difficulties in drug design and synthesis of macrocycle limit its applications. In this study, a series of macrocyclic derivatives designed from anaplastic lymphoma kinase (ALK) inhibitor lorlatinib were synthesized as Janus kinase 2 (JAK2) selective inhibitors. Among them, 17f had the best inhibitory activity (IC50 = 0.177 μmol·L–1) and selectivity for JAK2 over JAK1 and JAK3, which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhibitors.

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Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

Wei,

Lu,

Yao

et al. 2024

MedComm – Oncology

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Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure‐selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure‐based methods for discovering and designing selective JAKi. Other structure‐based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.

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Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

Cited by 12 publications

References 38 publications

Inhibitors Targeting Multiple Janus Kinases From Zanthoxylum simulans Mediate Inhibition and Apoptosis Against Gastric Cancer Cells via the Estrogen Pathway

Inhibitors Targeting Multiple Janus Kinases From Zanthoxylum simulans Mediate Inhibition and Apoptosis Against Gastric Cancer Cells via the Estrogen Pathway

Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

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