Discovery of 1-Methyl-1<i>H</i>-imidazole Derivatives as Potent Jak2 Inhibitors

Su, Qibin; Ioannidis, Stephanos; Chuaqui, Claudio; Almeida, Lynsie; Alimzhanov, Marat; Bebernitz, Geraldine; Bell, Kelly; Block, Michael H.; Howard, Tina D.; Huang, Shan; Huszar, Dennis; Read, Jon; Costa, Caroline; Shi, Jie; Su, Mei; Ye, Minwei; Zinda, Michael

doi:10.1021/jm401546n

Cited by 51 publications

(42 citation statements)

References 40 publications

(64 reference statements)

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“…In the current study, CIMO showed potent anticancer activity via the JAK2-STAT3 pathway; hence, we considered the possibility that CIMO interacts with the kinase domain of JAK2 directly. Thus, the JAK2 inhibitor 1-methyl-1H-imidazole, which modulated the JAK/STAT pathway, was considered for our studies (20). A molecular docking study was carried out to examine the possibility of CIMO binding to the kinase domain of JAK2.…”

Section: Cimo Suppresses the Growth Of Human Hcc In Vivo And Stat3 Acmentioning

confidence: 99%

“…The docking scores of the biologically active ligands with the kinase domain of JAK2 (Protein Data Bank entry 4C61) are summarized (Fig. 8A) (20). Based on Ligand Fit docking score calculations, CIMO shows a docking score of 95.07 kcal/mol, which is higher when compared with other structurally related azaspiranes.…”

Section: Cimo Suppresses the Growth Of Human Hcc In Vivo And Stat3 Acmentioning

confidence: 99%

“…Furthermore, it has been reported that staurosporines show strong JAK3 inhibition (19). Lestaurtinib is an orally bioavailable JAK2 inhibitor that is in phase II clinical trials for acute myeloid leukemia (20,21). However, the development of atiprimod has been stalled due to commercial reasons.…”

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confidence: 99%

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Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

Mohan

Bharathkumar

Bulusu

et al. 2014

Journal of Biological Chemistry

154

120

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Background: Constitutive activation of STAT3 is associated with the progression of hepatocellular carcinoma (HCC), and abrogation of STAT3 signaling is a potential target for HCC treatment. Results: A novel azaspirane modulates the JAK-STAT pathway in HCC. Conclusion:The lead compound induces apoptosis by down-regulating STAT3 signaling. Significance: This investigation reports a novel inhibitor of the JAK-STAT pathway with the potential to target various cancers.

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Section: Cimo Suppresses the Growth Of Human Hcc In Vivo And Stat3 Acmentioning

confidence: 99%

Section: Cimo Suppresses the Growth Of Human Hcc In Vivo And Stat3 Acmentioning

confidence: 99%

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Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

Mohan

Bharathkumar

Bulusu

et al. 2014

Journal of Biological Chemistry

154

120

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“…JAK2 is a member of Janus kinase and provides instructions for making a protein that promotes the growth and division (proliferation) of cells. In this study, the JAK2 was used as receptor and the chemical compounds used in herbal as the ligand [24]. This study will be based on the modification of our previously developed method [25][26][27].…”

Section: Mustarichie Et Almentioning

confidence: 99%

In-Silico Study of Bioactive Compounds of Natural Materials as a Jak- Signal Transducer and Activator of Transcription Inhibitor for Anti-Alopecia

Mustarichie

Megantara

Saptarini

2017

Asian J Pharm Clin Res

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Objective: This study aims to examine the compounds contained in herbs for the treatment of anti-alopecia by in-silico computation.Methods: JAK (Janus Kinase) regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. JAK2 which was a member of Janus family was used in this study as a receptor (PDB code: 4C61) and 15 compounds normally found in five herbals traditionally used as hair growth as ligands. Molecular modeling of bioactive compounds was performed using MarvinSketch and Prediction of physicochemical properties by ligand scout software. Molecular docking was performed using ligand scout, AutoDock Vina, and PyMOL. Binding affinity (Ei), inhibition constant (Ki), hydrogen bond interaction, and hydrophobic interaction were evaluated to find which of herbs potentially for anti-alopecia.Results: Among 15 compounds studied three of them, 6-hydroxy genistein, coreximine, and scoulerine interacted well with JAK2's active pocket so it can inhibit JAK-signal transducer and activator of transcription. 6-hydroxy genistein interacted with Asp994, Gly993 Met929, Val863, Leu983, Ala880, and Leu855 whereas coreximine and scoulerine interacted with Leu932, Pro933, Tyr931 and Pro933, Tyr931, Ala880, Val863, Leu983, Leu855, respectively. Conclusion:These results predicted that three compounds, namely, 6-hydroxy genistein, coreximine, and scoulerine which come from Dadap leaves (Erythrina variegata var. orientalis (L.) Merr.) were strongly had the link with JAK2 indicating that this plant extract may be used as hair growth agent/ anti-alopecia. As compounds studied was based on the literature survey, our results suggest compounds from six herbals studied should firstly be tested in-vivo for its anti-alopecia activity, fractionated, elucidated, to check as to whether their compounds responsible for anti-alopecia using the method developed in this paper.

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“…AstraZeneca recently reported an improved JAK2 inhibitor developed from AZD1480 [43]. Two major modifications were made to the original AZD1480 structure: first, the aminopyrazole on pyrimidine C4 was changed to aminoimidazole, which is expected to give the same binding interactions as AZD1480 to the hinge region of the ATP-binding site; second, the hydrophobic pocket of the pyrimidine ring was occupied with a fused bicyclic ring system.…”

Section: Key Termmentioning

confidence: 99%

Selective JAK Inhibitors

et al. 2014

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Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases.

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Discovery of 1-Methyl-1H-imidazole Derivatives as Potent Jak2 Inhibitors

Cited by 51 publications

References 40 publications

Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

In-Silico Study of Bioactive Compounds of Natural Materials as a Jak- Signal Transducer and Activator of Transcription Inhibitor for Anti-Alopecia

Selective JAK Inhibitors

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