2. Academic Validation
  3. Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis

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.
Olmo Martín-Cámara 1,  Marina Arribas 2,  Geoffrey Wells 3,  Marcos Morales-Tenorio 4,  Ángeles Martín-Requero 4 5,  Gracia Porras 4,  Ana Martínez 4 5,  Giorgio Giorgi 1,  Pilar López-Alvarado 1,  Isabel Lastres-Becker 2 5,  J Carlos Menéndez 1
Affiliations

Affiliations

  • 1 Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, Plaza de Ramón y Cajal sn, 28040 Madrid, Spain.
  • 2 Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Department of Biochemistry, School of Medicine, and Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
  • 3 UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX, United Kingdom.
  • 4 Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
  • 5 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain.
PMID: 34985276 DOI: 10.1021/acs.jmedchem.1c01255
Abstract

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.

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