Alkyl chain substituted 1,9-pyrazoloanthrones exhibit prominent inhibitory effect on c-Jun N-terminal kinase (JNK)

Karothu, Durga Prasad; Trinath, Jamma; Biswas, Arpita; Sekar, K.; Balaji, Kithiganahalli Narayanaswamy; Row, Tayur N. Guru

doi:10.1039/c4ob00548a

Cited by 4 publications

(2 citation statements)

References 34 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ginsenoside Rg1 (20 mg/kg/day), which inhibits JNK signalling, significantly promotes hepatic function and suppresses liver necrosis and inflammatory responses 78 . An azaquinolone analog168 and N-alkyl (propyl and butyl)-bearing pyrazoloanthrone scaffolds show promise as therapeutic inhibitors of JNK 79 . Angell et al 80 and Jang et al 81 further showed that N-(3cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides acts as an ATPbinding site-targeting inhibitor of JNK2 and JNK3.…”

Section: Jnk Inhibitors In the Treatment Of Cancermentioning

confidence: 99%

Selective inhibitors for JNK signalling: a potential targeted therapy in cancer

Jacević

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

116

View full text Add to dashboard Cite

c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context-and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment.

show abstract

Section: Jnk Inhibitors In the Treatment Of Cancermentioning

confidence: 99%

Selective inhibitors for JNK signalling: a potential targeted therapy in cancer

Jacević

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

116

View full text Add to dashboard Cite

show abstract

“…However these experiments showed reduced inhibitory activity21. In a recent study, we have demonstrated the enhancement of hydrophobic interactions in two specific N -alkyl derivatives of 1,9-pyrazoloanthrone (propyl (SPP1) and butyl (SPB1)) with inhibition of c -JNK at lower concentration values <10 μM, considerably lesser than the concentrations required to inhibit c -JNK by 1,9-pyrazoloanthrone29. It was also shown by Brydon et al, that substitution at the 7-position of 1,9-pyrazoloanthrone with a chlorine atom resulted in 2-fold improvement of inhibition21.…”

mentioning

confidence: 95%

Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock

Karothu

Trinath

Biswas

et al. 2014

Sci Rep

Self Cite

View full text Add to dashboard Cite

Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.

show abstract