RT Journal Article
T1 Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis
A1 Martín Cámara, Olmo
A1 Arribas Blázquez, Marina
A1 Wells, Geoffrey
A1 Morales-Tenorio, Marcos
A1 Martin Requero, Ángeles
A1 Porras, Gracia
A1 Martínez, Ana
A1 Giorgi, Giorgo
A1 López-Alvarado Gutiérrez, María Pilar
A1 Lastres Becker, Isabel
A1 Menéndez Ramos, José Carlos
AB Hybrid 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.
PB American Chemical Society
SN 0022-2623
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/96821
UL https://hdl.handle.net/20.500.14352/96821
LA eng
NO Martín-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.
NO Comunidad de Madrid 
NO Ministerio de Economía, Comercio y Empresa (España)
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Fundela Fundación Española Investigación Esclerosis Lateral
DS Docta Complutense
RD 23 ago 2024