Table 1.

Small molecules targeting the unfolded protein response (UPR) pathway for amyotrophic lateral sclerosis (ALS) treatment.

Small molecule	Molecular target	Model	Experimental evidence	Stage	References
Salubrinal	Block eIF2α dephosphorylation	SOD1G93A mice	Alleviation of disease manifestations and delayed progression	Preclinical	Saxena et al. (2009)
		Caenorhabditis elegans/zebrafish expressing TDP-43G348C	Response to neurotoxicity through reduction of ER stress. Rescue of the motor phenotype		Vaccaro et al. (2013)
		Neuro2a cells expressing SOD1G85R/SOD1G93A	Protects cells by suppressing the UPR that propagates as a death signal		Oh et al. (2008)
Arimoclomol	Coinducer of heat shock proteins	SOD1G93A mice	Improvement of muscle function and motor neuron(MN) survival	Fails phase III clinical trial	Kieran et al. (2004)
					Kalmar et al. (2008)
		ALS patients	Phase III clinical trial for 245 patients with ALS		https://clinicaltrials.gov/ct2/show/NCT03491462
PRE-084	Sigma-1 receptor agonist	SOD1G93A mice	Improvement of MN function	Preclinical	Mancuso et al. (2012)
			Functional preservation of MNs and an increase in the number of surviving MNs		Gaja-Capdevila et al. (2021)
		Zebrafish expressing TDP-43G348C	Restoration of motor performance and mitochondrial respiration		Lasbleiz et al. (2022)
Sephin1	Selective inhibitor of GADD34	SOD1G93A mice	Prevents motor deficits, motor neuron loss and molecular defects	Phase II clinical trial	Das et al. (2015)
		ALS patients	Treatment combining Riluzole and IFB-088 (sephin1) in bulbar-onset ALS		https://clinicaltrials.gov/ct2/show/NCT055080742
Guanabenz	Selective inhibitor of GADD34	SOD1G93A mice	Attenuation of ER stress and mitochondrial stress. Delayed disease onset and extended lifespan in SOD1 G93A mice.	Phase II clinical trial	Jiang et al. (2014)
					Wang et al. (2014)
		Caenorhabditis elegans/zebrafish expressing TDP-43G348C	Response to neurotoxicity through reduction of ER stress.		Vaccaro et al. (2013)
			Rescue of the motor phenotype
		ALS patients	200 patients within 18 months of onset of symptoms		Dalla Bella et al. (2021)
GSK2606414	Inhibit kinase domain of PERK	TDP-43 expressing Drosophila	Dramatic mitigation of TDP-43-induced climbing dysfunction	In vivo study	Kim et al. (2014)
		C9ORF72 expressing Drosophila	Inhibition of neurodegeneration in Drosophila		Zhang et al. (2018)
Cyclopiazonic acid	Specific inhibitor of SERCA	Motor neuron cultures from SOD1G93A mice	Helps maintain cellular ER homeostasis by suppressing ER calcium uptake and inducing UPR	In vitro study	Lautenschlager et al. (2013)