Identification and Structure—Activity Relationships of Substituted Pyridones as Inhibitors of Pim‐1 Kinase.

Cheney, I.W.; Yan, Shunqi; Appleby, T.C.; Walker, Heli; Vo, Todd; Yao, Nanhua; Hamatake, Robert; Hong, Zhi; Wu, Jim Zhen

doi:10.1002/chin.200730108

Cited by 22 publications

(37 citation statements)

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“…Our results confirm results from other investigations either in rabbits 29 or mice. 5,6 A major finding of the present study is that blockade of Pim-1 kinase using the highly selective 25 PIM-Inh.II completely abolishes DES-induced postconditioning and IPOST against myocardial infarction. The dosage of 10 mg/g body weight has recently been demonstrated to inhibit Pim-1 kinase activity effectively in mice in vivo.…”

Section: Desflurane-induced Postconditioning and Pim-1mentioning

confidence: 67%

“…In group 2 [dimethyl sulfoxide (DMSO)], the vehicle DMSO (10 ml/g) was injected intraperitoneally 5 min prior to the end of CAO. In group 3 [Pim-1 kinase inhibitor II (PIM-Inh.II)], the selective 25 Pim-1 kinase inhibitor 2-hydroxy-3-cyano-4-phenyl-6-(3-bromo-6-hydroxyphenyl)pyridine (PIM-Inh.II, 10 mg/g, dissolved in DMSO; Merck, Darmstadt, Germany) was administered intraperitoneally 5 min prior to the end of CAO. DES was administered at a concentration of 1.0 minimum alveolar concentration (MAC, 7.5 Vol% 26 ) for 18 min starting 3 min prior to the onset of reperfusion.…”

Section: Experimental Protocolmentioning

confidence: 99%

“…PIM-Inh.II has been demonstrated to be selective to Pim-1 kinase 25 with high selectivity over Pim-2 kinase. PIM-Inh.II was reported to have a half maximal inhibitory concentration (IC 50 ) for Pim-1 kinase of 50 nM, whereas the IC 50 for Pim-2 kinase was described to be > 20 mM.…”

Section: Desflurane-induced Postconditioning and Pim-1mentioning

confidence: 99%

“…PIM-Inh.II was reported to have a half maximal inhibitory concentration (IC 50 ) for Pim-1 kinase of 50 nM, whereas the IC 50 for Pim-2 kinase was described to be > 20 mM. 25 Nevertheless, potential effects of PIM-Inh.II on Pim-2 and Pim-3 kinase and other kinases involved in the signalling of either APOST or IPOST cannot be completely excluded. We did not measure Pim-1 activity directly.…”

Section: Desflurane-induced Postconditioning and Pim-1mentioning

confidence: 99%

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Desflurane‐induced and ischaemic postconditioning against myocardial infarction are mediated by Pim‐1 kinase

Stumpner

Smul

Redel

et al. 2012

Acta Anaesthesiol Scand

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Background: Anaesthetic-induced (APOST) and ischaemic postconditioning (IPOST) against myocardial infarction are mediated via phosphatidylinositol-3-kinase/Akt. Pim-1 kinase is acting downstream of Akt and has recently been demonstrated to enhance cardiomyocyte survival. We tested the hypothesis that both APOST and IPOST are mediated by Pim-1 kinase. Methods: Pentobarbital-anaesthetized male C57BL/6 mice were subjected to 45-min coronary artery occlusion (CAO) and 3-h reperfusion. Animals received either no intervention, the Pim-1 kinase inhibitor II (10 mg/g intraperitoneally) or its vehicle dimethy sulfoxide (10 ml/g intraperitoneally). Three minutes prior to the end of CAO, 1.0 minimum alveolar concentration desflurane was administered for 18 min alone or in combination with Pim-1 kinase inhibitor II. IPOST was induced by three cycles of each 10-s ischaemia/reperfusion, and animals received either IPOST alone or in combination with Pim-1 kinase inhibitor II. Infarct size was determined with triphenyltetrazolium chloride and area at risk with Evans blue. Protein expression of Pim-1 kinase, Bad, phospho-Bad Ser112 and B-cell

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Section: Desflurane-induced Postconditioning and Pim-1mentioning

confidence: 67%

Section: Experimental Protocolmentioning

confidence: 99%

Section: Desflurane-induced Postconditioning and Pim-1mentioning

confidence: 99%

Section: Desflurane-induced Postconditioning and Pim-1mentioning

confidence: 99%

See 2 more Smart Citations

Desflurane‐induced and ischaemic postconditioning against myocardial infarction are mediated by Pim‐1 kinase

Stumpner

Smul

Redel

et al. 2012

Acta Anaesthesiol Scand

View full text Add to dashboard Cite

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“…The Pim-1 protein is found both in the cytoplasm and in the nucleus. It was observed that Pim-1 protein is regulated by eIF 4E at post transcription stage and stabilized by Hsp90 and degraded by PP2A [3][4][5][6][7]. Pim-1 is a downstream effector of many cytokine signaling pathways and the expression of the Pim-1 gene is induced by a large set of cytokines [1].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Structure Activity Relationship and Molecular Docking of Pim-1 Kinase Inhibitors

Rathod¹

2017

Int J Biomed Data Min

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QSAR has established itself as an important means of virtual screening. Computational analysis of numerous drug molecules aided the facility to meaningfully screen specific ones for further use and experimentation. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) associated simulations were done and stochastic models were developed considering 55 molecules of hydroxyflavanone, thaizolidene2, 4-dione, pyridone derivatives against proviral insertion site of moloney murine leukemia virus. As part of the study, molecular field analysis (MFA) was done along with receptor surface analysis (RSA). Moreover, the generalization ability of the developed model was rigorously validated using 12 test set molecules. Molecular docking exercises were performed to analyze the protein structure using the crystal structure of PIM-1 kinase. Good correlation between predicted fitness scores and the observed activities was obtained. The presence of the hydroxyl groups in B ring instead of a ring was found crucial and playing important role for the compound activity. B ring substitution showed enhanced activity in this scenario. Further, the steric descriptor coefficient present near the ortho-position of N4 amine group indicates that any steric group increases the activity. GOLD was used for molecular docking of 55 molecules considered to target PIM-1 ATP binding site. GOLD based predicted fitness scores showed excellent correlation with the observations found in the available experimental outcomes.

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Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis‐inducing ability

Wang

Taniguchi

et al. 2010

Intl Journal of Cancer

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We previously demonstrated that Pim-3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim-3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl-X L . These observations prompted us to speculate that a chemical targeting Pim-3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low-molecule compounds by examining their capacity to inhibit Pim-3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim-3 kinase and its related kinases, such as Pim-1 and Pim-2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho-Ser 112 -Bad, but not total amounts of Bad and Pim-3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm-derived organs, particularly the pancreas.Pancreatic cancer is one of the most common causes of death from cancer. Most patients are diagnosed at an advanced stage; fewer than 20% of the patients present with potentially resectable cancer, whereas the remaining patients have locally advanced, unresectable or metastatic disease.

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Identification and Structure—Activity Relationships of Substituted Pyridones as Inhibitors of Pim‐1 Kinase.

Cited by 22 publications

References 1 publication

Desflurane‐induced and ischaemic postconditioning against myocardial infarction are mediated by Pim‐1 kinase

Desflurane‐induced and ischaemic postconditioning against myocardial infarction are mediated by Pim‐1 kinase

Quantitative Structure Activity Relationship and Molecular Docking of Pim-1 Kinase Inhibitors

Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis‐inducing ability

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