Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure–activity relationship

Xie, Jin; Poda, Gennadiy; Hu, Yonghan; Chen, Natalie X.; Heier, Richard F.; Wolfson, Serge G.; Reding, Matthew T.; Lennon, Patrick J.; Kurumbail, Ravi G.; Selness, Shaun R.; Li, Xiong; Kishore, Nandini; Sommers, Cynthia D.; Christine, Lori J.; Bonar, Sheri L.; Venkatraman, Neetu; Mathialagan, Sumathy; Brustkern, Sarah J.; Huang, Hengming

doi:10.1016/j.bmc.2010.12.027

Cited by 14 publications

(6 citation statements)

References 28 publications

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“…TPCA-1 exhibited better GR-enhancing activity than inhibitor VI. Furthermore, it has been extensively studied as an anti-inflammation agent in vitro and in vivo , and even proposed for a clinical trial to treat inflammation diseases 36 . To further confirm the effect of TPCA-1, we tested the effect of the GR antagonist RU486, which, as expected, reduced the inhibitory effect of Dex on NFkB (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our findings demonstrated synergistic effects of IKK2 inhibitors on GC-mediated NF- κ B repression. IKK2 inhibitors suppress NF-κB repression on their own and have been shown to suppress inflammation in vitro and in different models of inflammation diseases, including asthma and COPD 36 . Thus it would be of interest to further explore the combination of glucocorticoids and IKK2 inhibitors to reduce inflammation in asthma and other inflammation diseases.…”

Section: Discussionmentioning

confidence: 99%

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A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor

Jiang¹,

Dahlin

Weiss

et al. 2017

Sci Rep

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Glucocorticoids (GCs)—ligands of the glucocorticoid receptor (GR)—are widely used to treat inflammatory diseases, but suffer from significant side effects and poor responsiveness in certain patient populations. Identification of chemical GR modulators may provide insights into the regulatory mechanisms of anti-inflammatory functions of GR and help improve GC-based therapy. Here we report the development and application of a high-throughput screening to identify compounds that either enhance or suppress the anti-inflammatory effect of GR function. Using a cell-based GR activity assay that measures Dexamethasone (Dex)-mediated NF-κB repression, we have screened ~8,000 compounds and identified several compounds that suppressed GR activity, including multiple GSK3β inhibitors and anti-cancer agent camptothecin. Notably, we also identified two kinase IKK2 inhibitors, including TPCA-1, as GR enhancers that improve the anti-inflammatory effect of GR. In particular, TPCA-1 augmented the activity of Dex in NF-κB repression by attenuating GR down-regulation. Consistent with the observation, siRNA-mediated IKK2 knockdown decreased GR down-regulation and increased GR expression. Together, our results identified chemical compounds as novel modulators of GR and revealed an unexpected role for IKK2 in GR down-regulation. Furthermore, we have established a high-throughput screening platform for discovering GR-modulating compounds that may be repurposed to improve current GC-based therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor

Jiang¹,

Dahlin

Weiss

et al. 2017

Sci Rep

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“…The somewhat less favorable Pearson r of 0.56 for IKKA indicates this model to be less predictive than that for IKKB. Since the inhibitor data sets were obtained from 28 references (2002–2011 − ) listed in the BindingDB and the compounds from the same report always share high structural similarity, we considered the possibility that the FB-QSAR models are biased by the excessively focused structural frameworks. Thus, the two data sets were ordered by Canvas’s hierarchical clustering methodology.…”

Section: Resultsmentioning

confidence: 99%

Models for Predicting IKKA and IKKB Blockade

Snyder

2012

J. Chem. Inf. Model.

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We describe the application of different methods in the development of QSAR models for IKKA and IKKB inhibition. The results show that the best QSAR models provide highly accurate predictions for existing IkB-kinase (IKK) inhibitors. The exceptions, corresponding to 5% of the known collection of inhibitors, are five classes of compounds incorporating the nitrile or sulfonamide moieties, small compounds with molecular weights of less than 300, and two classes of blockers considered to be type II kinase inhibitors. Comparison of our novel IKKB homology model and the recently reported IKKB crystal structure implies that a predictive protein-antagonist complex structure is more likely to exist as an inactive form in the crystalline state as observed in the recent protein X-ray structure.

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“…While IKK2 knockout mice were not viable, B-cells obtained from conditional IKK2 knockout mice demonstrate severely decreased proliferation in response to stimulation with anti-IgM, LPS, or anti-CD40, mediators that activate NFκB in normal conditions [41]. Numerous IKK2 inhibitors are being evaluated as potential anti-inflammatory therapies, including IMD-0354, IMD-0650, BMS-345541, PS-1145, SC-514, ACHP, Bay 65-1942, and AS602868 [42], and while there have been no clinical trials using IKK2 inhibitors, in vitro IKK2 inhibitors decrease NFκB activation induced by both TNFα and viral exposure as well as expression of NFκB dependent genes ICAM-1, IL-8, RANTES, IP-10, I-TAC and COX-2 [43–45]. The IKK2 inhibitor PHA-408 fed to rats exposed to aerosolized LPS or cigarette smoke decreased NFκB –DNA binding as well as neutrophils and pro-inflammatory mediators TNFα, IL-6, GM-CSF and IL-1β BAL when compared to controls [46].…”

Section: Ikk2 Inhibitorsmentioning

confidence: 99%

p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

Banerjee¹,

Koziol‐White²,

Panettieri³

2012

Current Opinion in Pharmacology

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COPD represents a major respiratory disorder, causing significant morbidity and mortality throughout the world. While therapies exist for COPD, they are not always effective, and many patients experience exacerbations and morbidity despite current therapies. Study of the molecular mechanisms involved in the underlying physiological manifestations of COPD has yielded multiple new targets for therapeutic intervention. In this review, we discuss signaling pathways involved in COPD pathogenesis and review clinical studies of p38 MAPK inhibitors, TNFα inhibitors, and IKK2 inhibitors as potential COPD therapies.

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Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure–activity relationship

Cited by 14 publications

References 28 publications

A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor

A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor

Models for Predicting IKKA and IKKB Blockade

p38 MAPK inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD

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