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

被引：36

作者：

Brown, Dean G. ^{[1
]}

Shorter, James ^{[2
]}

Wobst, Heike J. ^{[3
]}

机构：

[1] AstraZeneca, BioPharmaceut R&D, Discovery Sci, Hit Discovery, Boston, MA USA

[2] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] AstraZeneca, BioPharmaceut R&D, Neurosci, Boston, MA USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 04期

关键词：

Amyotrophic lateral sclerosis; Frontotemporal dementia; PARP; TDP-43; Stress granules; POLY(ADP-RIBOSE) POLYMERASE PARP; DNA-BINDING PROTEIN; HEXANUCLEOTIDE REPEAT; PHASE-SEPARATION; LOBAR DEGENERATION; TDP-43; AUTOPHAGY; C9ORF72; ALS; PHOSPHORYLATION;

D O I：

10.1016/j.bmcl.2019.126942

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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(ADPribose) 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.

引用

页数：10

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