Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis

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dc.contributor.authorMartín Cámara, Olmo
dc.contributor.authorArribas Blázquez, Marina
dc.contributor.authorWells, Geoffrey
dc.contributor.authorMorales-Tenorio, Marcos
dc.contributor.authorMartin Requero, Ángeles
dc.contributor.authorPorras, Gracia
dc.contributor.authorMartínez, Ana
dc.contributor.authorGiorgi, Giorgo
dc.contributor.authorLópez-Alvarado Gutiérrez, María Pilar
dc.contributor.authorLastres Becker, Isabel
dc.contributor.authorMenéndez Ramos, José Carlos
dc.date.accessioned2024-01-30T22:22:29Z
dc.date.available2024-01-30T22:22:29Z
dc.date.issued2022
dc.description.abstractHybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.
dc.description.departmentDepto. de Farmacología y Toxicología
dc.description.facultyFac. de Veterinaria
dc.description.refereedTRUE
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipMinisterio de Economía, Comercio y Empresa (España)
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades (España)
dc.description.sponsorshipFundela Fundación Española Investigación Esclerosis Lateral
dc.description.statuspub
dc.identifier.citationMartín-Cámara O, Arribas M, Wells G, Morales-Tenorio M, Martín-Requero Á, Porras G, Martínez A, Giorgi G, López-Alvarado P, Lastres-Becker I, Menéndez JC. Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis. J Med Chem. 2022 Feb 10;65(3):1867-1882. doi: 10.1021/acs.jmedchem.1c01255. Epub 2022 Jan 5. PMID: 34985276; PMCID: PMC9132363.
dc.identifier.doi10.1021/acs.jmedchem.1c01255
dc.identifier.essn1520-4804
dc.identifier.issn0022-2623
dc.identifier.officialurlhttps://doi.orgi/10.1021/acs.jmedchem.1c01255
dc.identifier.urihttps://hdl.handle.net/20.500.14352/96821
dc.issue.number3
dc.journal.titleJournal of Medicinal Chemistry
dc.language.isoeng
dc.page.final1882
dc.page.initial1867
dc.publisherAmerican Chemical Society
dc.rights.accessRightsopen access
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco32 Ciencias Médicas
dc.titleMultitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number65
dspace.entity.typePublication
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relation.isAuthorOfPublication4c8ca147-677d-4846-97b7-d4419662ff60
relation.isAuthorOfPublication.latestForDiscovery86fc9e17-da09-40ce-8922-26515bf63722
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