Janus kinase 2 (JAK2) inhibitors in the treatment of multiple myeloma: modulating the myeloma immune microenvironment

2020 ◽  
Author(s):  
Hannah Giles ◽  
Guy Pratt
Keyword(s):  
Multiple Myeloma ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Immune Microenvironment ◽  
Jak2 Inhibitors

scholarly journals Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4393
Author(s):  
Saw Simeon ◽  
Nathjanan Jongkon
Keyword(s):  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Janus Kinase ◽  
Molecular Cluster ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Janus Kinase 2 ◽  
Structure Activity ◽  
Qsar Models ◽  
Jak2 Inhibitors

Janus kinase 2 (JAK2) inhibitors represent a promising therapeutic class of anticancer agents against many myeloproliferative disorders. Bioactivity data on pIC 50 of 2229 JAK2 inhibitors were employed in the construction of quantitative structure-activity relationship (QSAR) models. The models were built from 100 data splits using decision tree (DT), support vector machine (SVM), deep neural network (DNN) and random forest (RF). The predictive power of RF models were assessed via 10-fold cross validation, which afforded excellent predictive performance with R 2 and RMSE of 0.74 ± 0.05 and 0.63 ± 0.05, respectively. Moreover, test set has excellent performance of R 2 (0.75 ± 0.03) and RMSE (0.62 ± 0.04). In addition, Y-scrambling was utilized to evaluate the possibility of chance correlation of the predictive model. A thorough analysis of the substructure fingerprint count was conducted to provide insights on the inhibitory properties of JAK2 inhibitors. Molecular cluster analysis revealed that pyrazine scaffolds have nanomolar potency against JAK2.

The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3

2016 ◽  
Vol 24 (21) ◽  
pp. 5036-5046 ◽  
Author(s):  
Sun-Mi Lee ◽  
Kyoung Bin Yoon ◽  
Hyo Jeong Lee ◽  
Jiwon Kim ◽  
You Kyoung Chung ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Jak2 Inhibitors

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors

2012 ◽  
Vol 22 (24) ◽  
pp. 7653-7658 ◽  
Author(s):  
Timothy Forsyth ◽  
Patrick C. Kearney ◽  
Byung Gyu Kim ◽  
Henry W.B. Johnson ◽  
Naing Aay ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Janus Kinase 2 ◽  
In Vivo Evaluation ◽  
Jak2 Inhibitors

Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold

2019 ◽  
Vol 27 (8) ◽  
pp. 1562-1576 ◽  
Author(s):  
Yuan Yin ◽  
Cheng-Juan Chen ◽  
Ru-Nan Yu ◽  
Lei Shu ◽  
Tian-Tai Zhang ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Jak2 Inhibitors

scholarly journals As4S4 Exhibits Good Killing Effect on Multiple Myeloma Cells Via Repressing SOCS1 Methylation-Mediated JAK2/STAT3 Signaling Pathway

2019 ◽  
Vol 18 ◽  
pp. 153303381989680
Author(s):  
Di Wu ◽  
Wei Dong ◽  
Kun Fang ◽  
Mengchang Wang
Keyword(s):  
Multiple Myeloma ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Plasma Cells ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Suppressor Of Cytokine Signaling ◽  
Transcription 3

Objective: This study aimed to investigate the effect of tetra-arsenic tetra-sulfide on treating multiple myeloma and its potential regulation on suppressor of cytokine signaling 1 methylation-mediated Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. Methods: Tetra-arsenic tetra-sulfide with different concentrations were used to treat U266 cells, and cell viability was measured at 12, 24, and 48 hours with 0 μM tetra-arsenic tetra-sulfide treatment as control by Cell Counting Kit-8 assay. Suppressor of cytokine signaling 1 methylation and expression were determined by methylation-specific polymerase chain reaction, quantitative polymerase chain reaction, and Western blot, respectively, in U266 cells and normal plasma cells and in U266 cells treated by tetra-arsenic tetra-sulfide. Then, rescue experiments were performed by transfecting suppressor of cytokine signaling 1 small interfering RNA into tetra-arsenic tetra-sulfide-treated U266 cells. Besides, phosphor–Janus kinase 2, Janus kinase 2, phospho–signal transducer and activator of transcription 3, and signal transducer and activator of transcription 3 expressions were determined by Western blot. Results: Tetra-arsenic tetra-sulfide inhibited U266 cell viability efficiently in a dose- and time-dependent manner. Suppressor of cytokine signaling 1 methylation was higher while suppressor of cytokine signaling 1 expression was lower in U266 cells compared to normal plasma cells; when treated by tetra-arsenic tetra-sulfide, suppressor of cytokine signaling 1 methylation was decreased while suppressor of cytokine signaling 1 expression was increased in U266 cells, along with the reduced phospho–Janus kinase 2 and phospho–signal transducer and activator of transcription 3 expressions. Then, suppressor of cytokine signaling 1 small interfering RNA enhanced the cell viability and phospho–Janus kinase 2 as well as phospho–signal transducer and activator of transcription 3 expressions in both tetra-arsenic tetra-sulfide treatment-free and tetra-arsenic tetra-sulfide-treated U266 cells. Conclusion: Tetra-arsenic tetra-sulfide exhibits good killing effect on multiple myeloma cells via repressing suppressor of cytokine signaling 1 methylation and downstream Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, which might serve as a potential treatment option for multiple myeloma.

Applying Janus Kinase 2 (JAK2) Inhibitors to the Treatment of Chronic Myelofibrosis

2014 ◽  
Vol 14 (6) ◽  
pp. e229
Author(s):  
Srdan Verstovsek ◽  
Ross L. Levine ◽  
Brady L. Stein
Keyword(s):  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Jak2 Inhibitors
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