2. Academic Validation
  3. Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis

Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis

  • Bioorg Chem. 2025 Dec:167:109190. doi: 10.1016/j.bioorg.2025.109190.
Mohamed F Elmansy 1,  Pedro Soares 2,  Jose Ricardo D Dos Remedios 3,  Raghad Nowar 4,  Susan G Fox 5,  Anan Yu 5,  William L Klein 6,  Richard I Morimoto 5,  Richard B Silverman 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA; Organometallic and Organometalloid Chemistry Department, National Research Centre, 12622 Cairo, Egypt.
  • 2 Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
  • 3 Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA.
  • 4 Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
  • 5 Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA; Daniel F. and Ada L. Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
  • 6 Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA; Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA; Department of Neurology, Northwestern University, Chicago, IL 60611, USA.
  • 7 Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 41223590 DOI: 10.1016/j.bioorg.2025.109190
Abstract

Amyotrophic lateral sclerosis (ALS) is a fast-progressing disease characterized by the loss of voluntary movements and death due to respiratory failure. The presence of protein aggregates is a major hallmark of the disease. Hence, targeting the pathological protein aggregation may provide more efficient therapeutics for ALS. Recently, we reported a cyclohexane-1,3-dione (NU-9) with in vitro anti-aggregation capacity and promising in vivo efficacy in ALS animal models, which validated our approach toward the development of novel and potentially more effective ALS therapeutics. Herein, we report the design and synthesis of a new series of small-molecule derivatives of NU-9 and the evaluation of their in vitro anti-aggregation activity in a PC12 cellular model containing an SOD1G85R familial ALS mutation. The most promising compound (20) presented an in vitro anti-aggregation potency comparable to that of NU-9. Moreover, the better in vitro BBB permeability, microsomal stability, and toxicity profile of 20 also suggests a potentially higher efficacy in vivo.

Keywords

Amyotrophic lateral sclerosis; Cyclohexane-1,3-diones; Protein aggregation; SOD-1; Small-molecules.

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