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

Dean G Brown; James Shorter; Heike J Wobst

doi:10.1016/j.bmcl.2019.126942

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

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126942. doi: 10.1016/j.bmcl.2019.126942. Epub 2019 Dec 30.

Authors

Dean G Brown¹, James Shorter², Heike J Wobst³

Affiliations

¹ Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Boston, United States. Electronic address: dbrown@jnanatx.com.
² Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
³ Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, United States. Electronic address: hwobst@jnanatx.com.

PMID: 31926785
DOI: 10.1016/j.bmcl.2019.126942

Abstract

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.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; PARP; Stress granules; TDP-43.

Publication types

Review

MeSH terms

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 / drug therapy*
Frontotemporal Dementia / genetics
Frontotemporal Dementia / pathology
Humans
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*

Substances

C9orf72 Protein
C9orf72 protein, human
DNA-Binding Proteins
Poly(ADP-ribose) Polymerase Inhibitors
Protein Kinase Inhibitors
Small Molecule Libraries
TARDBP protein, human
Poly(ADP-ribose) Polymerases