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

  • Nitro 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.

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Author:Matthias Piesche, Jessica RoosGND, Benjamin Kühn, Jasmin Fettel, Nadine HellmuthGND, Camilla Brat, Isabelle Viktoria Maucher, Omar Awad, Carmela Matrone, Simon Gabriel Comerma Steffensen, Georg ManolikakesORCiDGND, Ulrike Heinicke, Kai ZacharowskiORCiDGND, Dieter SteinhilberORCiDGND, Thorsten Jürgen MaierGND
URN:urn:nbn:de:hebis:30:3-561296
DOI:https://doi.org/10.3389/fphar.2020.01297
ISSN:1663-9812
Parent Title (English):Frontiers in pharmacology
Publisher:Frontiers
Place of publication:Lausanne
Document Type:Article
Language:English
Date of Publication (online):2020/09/03
Date of first Publication:2020/09/03
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/09/24
Tag:Michael acceptor; covalent drugs; electrophilic fatty acids; nitroalkylation; post-translational modifications
Volume:11
Issue:art. 1297
Article Number:1297
Page Number:16
First Page:1
Last Page:16
Note:
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
HeBIS-PPN:47077276X
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0