4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade

Pippione, Agnese Chiara; Federico, Antonella; Ducime, Alex; Sainas, Stefano; Boschi, Donatella; Lupino, Elisa; Piccinini, Marco; Kubbutat, Michael H.G.; Contreras, Jean Marie; Morice, Christophe; Al-Karadaghi, Salam; Lolli, Marco Lucio

doi:10.1039/c7md00278e

Cited by 22 publications

(19 citation statements)

References 33 publications

(47 reference statements)

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“…However, questions surrounding the true molecular target of these compounds has been raised by the lack of conclusive biochemical evidence for IKKβ antagonism. Indeed, IMD-0354 was recently shown to exhibit no activity against IKKβ or IKKα in an ATP-based kinase assay [ 125 ].…”

Section: Pre-clinical Development Of Ikkβ Inhibitorsmentioning

confidence: 99%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

108

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Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.

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Section: Pre-clinical Development Of Ikkβ Inhibitorsmentioning

confidence: 99%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

108

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“…The NF-κB pathway can be regulated by exogenous molecules at many levels, and thus several compounds have been developed for inhibition of its activation. Pippione et al [ 11 ] recently discovered a new molecule (herein after referred to as MEDS-23) capable of specifically inhibiting the canonical NF-κB cascade at a nanomolar concentration (IC 50 = 143 nM). Starting from the chemical IMD-0354 ( Figure S1 ), a well-known NF-κB inhibitor [ 12 , 13 , 14 ], they used an acidic hydroxylated azole to mimic the electron withdrawing substituted phenol.…”

Section: Introductionmentioning

confidence: 99%

“…This technique, called bioisosteric scaffold hopping, allows for obtaining compounds with modulated acidity and lipophilicity, hydrogen bond donor/acceptor capability, orientation of substituents and, consequently, can improve interaction with the target and/or in-vivo pharmacokinetic parameters [ 15 , 16 , 17 ]. Pippione et al [ 11 , 18 ] reported that both MEDS-23 and IMD-0354 were inactive against isolated IKKβ enzymes but were both able to block the degradation of IκBα after inflammatory stimulus (TNFα) in Jurkat cells.…”

Section: Introductionmentioning

confidence: 99%

A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

et al. 2021

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Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

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“…Aberrant activation of NF-κB has been implicated in the pathogenesis of lung cancer cells (Chen, Bai, & Lin, 2012;Denlinger, Rundall, & Jones, 2004;Wong, Jacks, & Dranoff, 2010). Therefore, targeting NF-κB has a potential to be an efficient approach in antitumor treatment (Pippione et al, 2017(Pippione et al, , 2018.…”

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confidence: 99%

Design and optimize N‐substituted EF24 as effective and low toxicity NF‐κB inhibitor for lung cancer therapy via apoptosis‐to‐pyroptosis switch

Chen

Zheng

et al. 2019

Chem Biol Drug Des

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As NF‐κB signaling pathway is constitutively activated in lung cancer, targeting NF‐κB has a potential for the treatment. EF24 has been proved to be a NF‐κB inhibitor with good antitumor activity, while whose toxicity possibly became one of the obstacles to enter into clinical application. In order to find high efficiency and low toxicity NF‐κB inhibitors, EF24 was modified and 13d was screened out. It was proved that 13d possessed an effective combination of inhibiting NF‐κB pathway and showing lower cytotoxicity on normal cells as well as less toxicity in acute toxicity experiment compared with the lead compound of EF24. In addition, 13d was found to inhibit cell vitality, arrest cell cycle in G2/M phase, promote cell apoptosis, and suppress the xenograft tumor growth. Furthermore, 13d was elucidated to induce pyroptosis developing from apoptosis, which was associated with the inhibition of NF‐κB. Taken together, it was suggested that 13d was a potent antitumor agent.

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4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade

Cited by 22 publications

References 33 publications

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

Design and optimize N‐substituted EF24 as effective and low toxicity NF‐κB inhibitor for lung cancer therapy via apoptosis‐to‐pyroptosis switch

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