posted on 2022-01-05, 15:52authored byOlmo Martín-Cámara, Marina Arribas, Geoffrey Wells, Marcos Morales-Tenorio, Ángeles Martín-Requero, Gracia Porras, Ana Martínez, Giorgio Giorgi, Pilar López-Alvarado, Isabel Lastres-Becker, J. Carlos Menéndez
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.