Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury

Krenitsky, Veronique Plantevin; Delgado, Mercedes; Nadolny, Lisa; Sahasrabudhe, Kiran; Ayala, Leticia; Clareen, Steven S.; Hilgraf, Robert; Albers, Ronald; Kois, Adam; Hughes, Kevin; Wright, Jonathan; Nowakowski, Jacek; Sudbeck, Elise A.; Ghosh, Sutapa; Bahmanyar, Sogole; Chamberlain, Philip P.; Muir, Jeff; Cathers, Brian E.; Giegel, David A.; Xu, Li; Celeridad, Maria; Moghaddam, Mehran F.; Khatsenko, Oleg G.; Omholt, P.; Katz, Jason D.; Pai, S.; Fan, R.; Tang, Yang; Shirley, Michael A.; Benish, Brent; Blease, Kate; Raymon, Heather K.; Bhagwat, Shripad S.; Henderson, Ian; Cole, Andrew G.; Bennett, Brydon L.; Satoh, Yoshitaka

doi:10.1016/j.bmcl.2011.12.028

Cited by 30 publications

(16 citation statements)

References 31 publications

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“…Several synthetic inhibitors of enzymatic activity of JNK have been described, including small molecules SP600125, AS601245, IQ-1S, SR-3306; protein and non-protein molecules inhibiting the interactions between JNK and their substrates or between JNK and the folding proteins and/or cellular organelles have been proposed as well (Irving and Bamford, 2002 ; Carboni et al, 2004 , 2005 ; Gao et al, 2005 ; Guan et al, 2005 ; Kuan and Burke, 2005 ; Pan et al, 2005 ; Krenitsky et al, 2012 ; Schepetkin et al, 2012 ; Gehringer et al, 2015 ). However, a search for highly selective JNK inhibitors, suitable for therapeutic purposes continues.…”

Section: Effects Of Modulation Of Jnk Activitymentioning

confidence: 99%

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

et al. 2018

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In this article, we review the literature regarding the role of c-Jun N-terminal kinases (JNKs) in cerebral and myocardial ischemia/reperfusion injury. Numerous studies demonstrate that JNK-mediated signaling pathways play an essential role in cerebral and myocardial ischemia/reperfusion injury. JNK-associated mechanisms are involved in preconditioning and post-conditioning of the heart and the brain. The literature and our own studies suggest that JNK inhibitors may exert cardioprotective and neuroprotective properties. The effects of modulating the JNK-depending pathways in the brain and the heart are reviewed. Cardioprotective and neuroprotective mechanisms of JNK inhibitors are discussed in detail including synthetic small molecule inhibitors (AS601245, SP600125, IQ-1S, and SR-3306), ion channel inhibitor GsMTx4, JNK-interacting proteins, inhibitors of mixed-lineage kinase (MLK) and MLK-interacting proteins, inhibitors of glutamate receptors, nitric oxide (NO) donors, and anesthetics. The role of JNKs in ischemia/reperfusion injury of the heart in diabetes mellitus is discussed in the context of comorbidities. According to reviewed literature, JNKs represent promising therapeutic targets for protection of the brain and the heart against ischemic stroke and myocardial infarction, respectively. However, different members of the JNK family exert diverse physiological properties which may not allow for systemic administration of non-specific JNK inhibitors for therapeutic purposes. Currently available candidate JNK inhibitors with high therapeutic potential are identified. The further search for selective JNK3 inhibitors remains an important task.

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Section: Effects Of Modulation Of Jnk Activitymentioning

confidence: 99%

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

et al. 2018

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“…Finally, we thought to fluorination as a way to improve the cellular potency of compound 1 as the introduction of fluorine atoms in proper positions of a given molecule is a successful strategy used in drug design to improve the physicochemical and ADME properties of a lead compound . Indeed, several fluorinated drugs entered clinical trials , and it has been reported that approximately 20% of the marketed drugs contain at least one fluorine atom, including the top‐selling drug Lipitor . We indeed synthesized the polyfluorinated compounds 47 – 55, of which compounds 47 – 49 showed in vitro AKT1 inhibition (Table ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and SAR Studies of Dual AKT/NF‐κB Inhibitors Against Melanoma

Barile

Feng

et al. 2013

Chem Biol Drug Des

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The AKT and NF-κB pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways. Here we describe SAR studies that led to novel fluorinated derivatives with increased cellular potency, reflected in efficient inhibition of AKT and IKKs. Selected compounds demonstrated effective toxicity on melanoma, breast and prostate cell lines. Finally, a representative derivative showed promising efficacy in an in vivo melanoma xenograft model.

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“…Various nonprotein synthetic inhibitors of JNK enzymatic activity are described including SP600125, AS601245, IQ-1S, SR-3306, and SU3327 as well as protein and nonprotein molecules inhibiting interactions of JNKs with their substrates, folding proteins, and/or cell organelles [ 9 , 35 , 38 , 43 , 44 , 45 , 46 , 47 ]. Some of them demonstrated neuroprotective activity in the animal models of stroke [ 7 , 48 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia

Плотников

Чернышева

Smol’yakova

et al. 2020

Cells

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A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

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Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury

Cited by 30 publications

References 31 publications

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

Synthesis and SAR Studies of Dual AKT/NF‐κB Inhibitors Against Melanoma

Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia

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