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The emerging therapeutic potential of nitro fatty acids and other michael acceptor-containing drugs for the treatment of inflammation and cancer

dc.contributor.authorPiesche, Matthias
dc.contributor.authorRoos, Jessica
dc.contributor.authorKühn, Benjamin
dc.contributor.authorFettel, Jasmin
dc.contributor.authorHellmuth, Nadine
dc.contributor.authorBrat, Camilla
dc.contributor.authorMaucher, Isabelle V.
dc.contributor.authorAwad, Omar
dc.contributor.authorMatrone, Carmela
dc.contributor.authorComerma-Steffensen, Simon G.
dc.contributor.authorManolikakes, Georg
dc.contributor.authorHeinicke, Ulrike
dc.contributor.authorZacharowski, Kai D.
dc.contributor.authorSteinhilber, Dieter
dc.contributor.authorMaier, Thorsten J.
dc.date.accessioned2021-11-12T19:23:00Z
dc.date.available2021-11-12T19:23:00Z
dc.date.issued2020
dc.identifier.urihttp://repositorio.ucm.cl/handle/ucm/3469
dc.description.abstractNitro fatty acids (NFAs) are endogenously generated lipid mediators deriving from reactions of unsaturated electrophilic fatty acids with reactive nitrogen species. Furthermore, Mediterranean diets can be a source of NFA. These highly electrophilic fatty acids can undergo Michael addition reaction with cysteine residues, leading to post-translational modifications (PTM) of selected regulatory proteins. Such modifications are capable of changing target protein function during cell signaling or in biosynthetic pathways. NFA target proteins include the peroxisome proliferator-activated receptor γ (PPAR-γ), the pro-inflammatory and tumorigenic nuclear factor-κB (NF-κB) signaling pathway, the pro-inflammatory 5-lipoxygenases (5-LO) biosynthesis pathway as well as soluble epoxide hydrolase (sEH), which is essentially involved in the regulation of vascular tone. In several animal models of inflammation and cancer, the therapeutic efficacy of well-tolerated NFA has been demonstrated. This has already led to clinical phase II studies investigating possible therapeutic effects of NFA in subjects with pulmonary arterial hypertension. Albeit Michael acceptors feature a broad spectrum of bioactivity, they have for a rather long time been avoided as drug candidates owing to their presumed unselective reactivity and toxicity. However, targeted covalent modification of regulatory proteins by Michael acceptors became recognized as a promising approach to drug discovery with the recent FDA approvals of the cancer therapeutics, afatanib (2013), ibrutinib (2013), and osimertinib (2015). Furthermore, the Michael acceptor, neratinib, a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor, was recently approved by the FDA (2017) and by the EMA (2018) for the treatment of breast cancer. Finally, a number of further Michael acceptor drug candidates are currently under clinical investigation for pharmacotherapy of inflammation and cancer. In this review, we focus on the pharmacology of NFA and other Michael acceptor drugs, summarizing their potential as an emerging class of future antiphlogistics and adjuvant in tumor therapeutics.es_CL
dc.language.isoenes_CL
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
dc.sourceFrontiers in Pharmacology, 11, 1297es_CL
dc.subjectCovalent drugses_CL
dc.subjectElectrophilic fatty acidses_CL
dc.subjectMichael acceptores_CL
dc.subjectNitroalkylationes_CL
dc.subjectPost-translational modificationses_CL
dc.titleThe emerging therapeutic potential of nitro fatty acids and other michael acceptor-containing drugs for the treatment of inflammation and canceres_CL
dc.typeArticlees_CL
dc.ucm.indexacionScopuses_CL
dc.ucm.indexacionIsies_CL
dc.ucm.uriwww.frontiersin.org/articles/10.3389/fphar.2020.01297/fulles_CL
dc.ucm.doidoi.org/10.3389/fphar.2020.01297es_CL


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Atribución-NoComercial-SinDerivadas 3.0 Chile
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