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

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

scholarly journals Erythropoietin Attenuates Experimental Contrast-Induced Nephrology: A Role for the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Jia Yang ◽  
Jiaojiao Zhou ◽  
Xin Wang ◽  
Ling Ji ◽  
Siwen Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Janus Kinase ◽  
Cell Counting ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Protein Levels ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Transcription 3

The aim of the present study was to investigate the effect of erythropoietin (EPO) on contrast-induced nephrology (CIN) in vivo and in vitro. Male C57BL/6J mice were divided into four groups: control, CIN (iohexol 6.0 g/kg), EPO (3,000 IU/kg), and CIN+EPO. Hematoxylin and eosin (H&E) staining and biochemical index analyses were performed to evaluate renal injury. The cellular proliferation rate was detected using the Cell Counting Kit-8 (CCK-8) assay. In addition, a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometric assay were used to assess the apoptosis of tissue and cells, respectively. Renal protein expression associated with apoptosis, pyroptosis, and signaling pathways was determined by Western blot (WB) assays for tissues and cells. The results showed that EPO significantly decreased serum creatinine, blood urea nitrogen, and cystatin C levels and alleviated renal histological changes in vivo. The protein levels of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway components were overexpressed in the EPO treatment group. Furthermore, EPO suppressed the cell apoptosis and pyroptosis; decreased the protein levels of cleaved caspase-3, Bax, gasdermin D (GSDMD), and caspase-1; and enhanced the expression of Bcl-2. In summary, EPO could exert renoprotective effect by activating the JAK2/STAT3 signaling pathway, which may be a novel potential therapy for the treatment of CIN in the clinic.

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

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

scholarly journals Pro-protein convertase subtilisin/kexin type 9 promotes intestinal tumor development by activating Janus kinase 2/signal transducer and activator of transcription 3/SOCS3 signaling in ApcMin/+ mice

2021 ◽  
Vol 35 ◽  
pp. 205873842110383
Author(s):  
Kai Yang ◽  
Jie Zhu ◽  
Huan-hua Luo ◽  
Shu-wen Yu ◽  
Lu Wang
Keyword(s):  
Colorectal Cancer ◽  
Density Lipoprotein ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Intestinal Tumor ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Intestinal Tumors ◽  
Transcription 3

Introduction Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipoprotein homeostasis in humans. Evolocumab is a selective PCSK9 inhibitor that can reduce low-density lipoprotein cholesterol (LDLC) level and decrease hypercholesterolemia. The current study aimed to explore whether PCSK9 increases the risk of colorectal cancer. Methods First, we utilized the classic intestinal tumor ApcMin/+ mouse model and PCSK9 knock-in (KI) mice to establish ApcMin/+PCSK9(KI) mice. Then, we investigated the effect of PCSK9 overexpression in ApcMin/+PCSK9(KI) mice and PCSK9 inhibition using evolocumab on the progression of intestinal tumors in vivo by hematoxylin and eosin (HE) staining, Western blot, and immunohistochemistry (IHC) assay. Results ApcMin/+PCSK9(KI) mice had higher numbers and larger sizes of adenomas, with 83.3% of these mice developing adenocarcinoma (vs. 16.7% of ApcMin/+ mice). However, treatment with evolocumab reduced the number and size of adenomas and prevented the development of adenocarcinomas in ApcMin/+ mice. PCSK9 overexpression reduced tumor cell apoptosis, the Bax/bcl-2 ratio, and the levels of cytokine signaling 3 protein (SOCS3) suppressors, but activated Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in intestinal tumors. In contrast, evolocumab treatment had the opposite effect on ApcMin/+mice. Conclusion PCSK9 might act as an oncogene or have an oncogenic role in the development and progression of colorectal cancer in vivo via activation of JAK2/STAT3/SOCS3 signaling.

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