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Updated: Jan 7, 2026

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Desarrollo de Fármacos

Wenyan Lu1, Thomas R Caulfield1, Suren Jeevaratnam1

  • 1Mayo Clinic, Jacksonville, FL, USA.

Alzheimer's & dementia : the journal of the Alzheimer's Association
|December 25, 2025
PubMed
Resumen
Este resumen es generado por máquina.

Un nuevo candidato a fármaco de doble acción, W2A-28, se dirige simultáneamente a la inhibición de la histona deacetilasa (HDAC) y a la activación de la señalización Wnt/β-catenina. Este compuesto muestra potencial para el tratamiento de la enfermedad de Alzheimer (EA) al reducir las patologías de amiloide-beta y tau.

Palabras clave:
Enfermedad de AlzheimerInhibidores de histona deacetilasaDesarrollo de fármacosSeñalización WntOrganoidesCélulas madre pluripotentes inducidas

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Área de la Ciencia:

  • Neurociencia; Farmacología; Biología Molecular

Sus antecedentes:

  • La enfermedad de Alzheimer (EA) implica un deterioro de la acetilación de histonas y la señalización Wnt/β-catenina.; La focalización de patologías múltiples, como con moduladores duales, puede ofrecer efectos sinérgicos para la EA.; Los inhibidores de histona deacetilasa (HDAC) de clase I y los activadores de la vía Wnt/β-catenina son terapéuticos potenciales para la EA.

Objetivo del estudio:

  • Desarrollar moduladores duales novedosos dirigidos a la inhibición de HDAC de clase I y la activación de la señalización Wnt/β-catenina.; Evaluar el potencial terapéutico del compuesto líder W2A-28 en modelos de enfermedad de Alzheimer (EA).

Principales métodos:

  • Se utilizó CI-994 como andamio para diseñar compuestos de doble acción.; Se evaluó la actividad inhibidora de W2A-28 contra las HDAC de clase I y su efecto sobre la actividad del reportero Wnt.; Se determinó el impacto de W2A-28 en los niveles de proteína LRP6, solubilidad, estabilidad y permeabilidad.; Se probó W2A-28 en organoides cerebrales derivados de células madre pluripotentes inducidas (iPSC) de pacientes.

Principales resultados:

  • W2A-28 inhibió potentemente las HDAC de clase I (HDAC1, 2 y 3) con valores de IC50 en nanomolar.; W2A-28 activó la señalización Wnt/β-catenina al aumentar la actividad del reportero Wnt y estabilizar LRP6.; El compuesto exhibió propiedades farmacocinéticas favorables, incluyendo buena solubilidad, estabilidad y permeabilidad.; W2A-28 redujo significativamente los niveles de amiloide-beta (Aβ40, Aβ42) y suprimió la fosforilación de tau en organoides de EA.

Conclusiones:

  • W2A-28 demuestra propiedades duales inhibidoras y activadoras relevantes para la patología de la EA.; El compuesto redujo eficazmente biomarcadores clave de la enfermedad de Alzheimer en organoides derivados de pacientes.; W2A-28 representa un candidato a fármaco prometedor para el tratamiento de la enfermedad de Alzheimer.