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 w...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-09-01
|
Series: | Frontiers in Pharmacology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.01297/full |
id |
doaj-3145053a7c004ee280edc9ef3a6adcaa |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthias Piesche Matthias Piesche Jessica Roos Jessica Roos Benjamin Kühn Jasmin Fettel Nadine Hellmuth Camilla Brat Isabelle V. Maucher Omar Awad Carmela Matrone Simon Gabriel Comerma Steffensen Simon Gabriel Comerma Steffensen Georg Manolikakes Ulrike Heinicke Kai D. Zacharowski Dieter Steinhilber Thorsten J. Maier Thorsten J. Maier |
spellingShingle |
Matthias Piesche Matthias Piesche Jessica Roos Jessica Roos Benjamin Kühn Jasmin Fettel Nadine Hellmuth Camilla Brat Isabelle V. Maucher Omar Awad Carmela Matrone Simon Gabriel Comerma Steffensen Simon Gabriel Comerma Steffensen Georg Manolikakes Ulrike Heinicke Kai D. Zacharowski Dieter Steinhilber Thorsten J. Maier Thorsten J. Maier The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer Frontiers in Pharmacology covalent drugs electrophilic fatty acids Michael acceptor nitroalkylation post-translational modifications |
author_facet |
Matthias Piesche Matthias Piesche Jessica Roos Jessica Roos Benjamin Kühn Jasmin Fettel Nadine Hellmuth Camilla Brat Isabelle V. Maucher Omar Awad Carmela Matrone Simon Gabriel Comerma Steffensen Simon Gabriel Comerma Steffensen Georg Manolikakes Ulrike Heinicke Kai D. Zacharowski Dieter Steinhilber Thorsten J. Maier Thorsten J. Maier |
author_sort |
Matthias Piesche |
title |
The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer |
title_short |
The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer |
title_full |
The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer |
title_fullStr |
The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer |
title_full_unstemmed |
The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer |
title_sort |
emerging therapeutic potential of nitro fatty acids and other michael acceptor-containing drugs for the treatment of inflammation and cancer |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2020-09-01 |
description |
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. |
topic |
covalent drugs electrophilic fatty acids Michael acceptor nitroalkylation post-translational modifications |
url |
https://www.frontiersin.org/article/10.3389/fphar.2020.01297/full |
work_keys_str_mv |
AT matthiaspiesche theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT matthiaspiesche theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT jessicaroos theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT jessicaroos theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT benjaminkuhn theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT jasminfettel theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT nadinehellmuth theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT camillabrat theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT isabellevmaucher theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT omarawad theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT carmelamatrone theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT simongabrielcomermasteffensen theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT simongabrielcomermasteffensen theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT georgmanolikakes theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT ulrikeheinicke theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT kaidzacharowski theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT dietersteinhilber theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT thorstenjmaier theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT thorstenjmaier theemergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT matthiaspiesche emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT matthiaspiesche emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT jessicaroos emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT jessicaroos emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT benjaminkuhn emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT jasminfettel emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT nadinehellmuth emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT camillabrat emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT isabellevmaucher emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT omarawad emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT carmelamatrone emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT simongabrielcomermasteffensen emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT simongabrielcomermasteffensen emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT georgmanolikakes emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT ulrikeheinicke emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT kaidzacharowski emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT dietersteinhilber emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT thorstenjmaier emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer AT thorstenjmaier emergingtherapeuticpotentialofnitrofattyacidsandothermichaelacceptorcontainingdrugsforthetreatmentofinflammationandcancer |
_version_ |
1724591633528258560 |
spelling |
doaj-3145053a7c004ee280edc9ef3a6adcaa2020-11-25T03:26:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-09-011110.3389/fphar.2020.01297548766The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and CancerMatthias Piesche0Matthias Piesche1Jessica Roos2Jessica Roos3Benjamin Kühn4Jasmin Fettel5Nadine Hellmuth6Camilla Brat7Isabelle V. Maucher8Omar Awad9Carmela Matrone10Simon Gabriel Comerma Steffensen11Simon Gabriel Comerma Steffensen12Georg Manolikakes13Ulrike Heinicke14Kai D. Zacharowski15Dieter Steinhilber16Thorsten J. Maier17Thorsten J. Maier18Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, ChileOncology Center, Medicine Faculty, Catholic University of Maule, Talca, ChileDepartment of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen, GermanyDepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main, GermanyDepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, GermanyDepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main, GermanyDepartment of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen, GermanyDivision of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, ItalyDepartment of Biomedicine, Medicine Faculty, Aarhus University, Aarhus, DenmarkAnimal Physiology, Department of Biomedical Sciences, Veterinary Faculty, Central University of Venezuela, Maracay, VenezuelaDepartment of Organic Chemistry, Technical University Kaiserslautern, Kaiserslautern, GermanyDepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, GermanyDepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University, Frankfurt am Main, GermanyDepartment of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen, GermanyDepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, GermanyNitro 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.https://www.frontiersin.org/article/10.3389/fphar.2020.01297/fullcovalent drugselectrophilic fatty acidsMichael acceptornitroalkylationpost-translational modifications |