Emerging small-molecule therapeutic approaches for amyotrophic lateral sclerosis and frontotemporal dementia

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 4; p. 126942
• Main Authors: Brown, Dean G., Shorter, James, Wobst, Heike J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.02.2020
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Autophagy - drug effects; C9orf72 Protein - antagonists & inhibitors; C9orf72 Protein - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Frontotemporal dementia; Frontotemporal Dementia - drug therapy; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Humans; PARP; Poly(ADP-ribose) Polymerase Inhibitors - chemistry; Poly(ADP-ribose) Polymerase Inhibitors - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Poly(ADP-ribose) Polymerases - chemistry; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Stress granules; TDP-43; Amyotrophic lateral sclerosis; PARP; Frontotemporal dementia; Stress granules; TDP-43
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.126942

Novel treatments are desperately needed for ALS and FTD. A survey of emerging small molecule approaches to ALS therapy is provided, along with a perspective on these opportunities. [Display omitted] Novel treatments are desperately needed for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review article, a survey of emerging small-molecule approaches for ALS and FTD therapies is provided. These approaches include targeting aberrant liquid-liquid phase separation and stress granule assembly, modulation of RNA-protein interactions, inhibition of TDP-43 phosphorylation, inhibition of poly(ADP-ribose) polymerases (PARP), RNA-targeting approaches to reduce RAN translation of dipeptide repeat proteins from repeat expansions of C9ORF72, and novel autophagy activation pathways. This review details the emerging small-molecule tools and leads in these areas, along with a critical perspective on the key challenges facing these opportunities.