TABLE 2

Integrated stress response (ISR)-modifying drugs

	Drug	Putative mode of action	Cautions	References
ISR inhibitors
PERK	GSK2656157	Targets ATP binding site of PERK	Inhibits RIPK1	[68, 69]
	GSK2606414	Targets ATP binding site of PERK	Inhibits RIPK1 and PKR Weakly activates GCN2	[69, 70]
	4-PBA	Reduces ER stress by unclear mechanism	Affects all arms of the UPR	[71]
	TUDCA	Reduces ER stress by unclear mechanism	Affects all arms of the UPR	[71]
HRI	Aminopyrazolindane		Not commercially available	[72]
PKR	C16	Targets ATP binding site of PKR		[73]
	C22	Targets ATP binding site of PKR		[73]
	2-Aminopurine	Targets ATP binding site of PKR		[74]
GCN2	6D	Targets ATP binding site of GCN2	Not commercially available	[75]
	6E (aka GCN2iA)	Targets ATP binding site of GCN2	Not commercially available	[75, 76]
eIF2β	ISRIB	Stablises eIF2β dimers	Cell lines can acquire ISRIB resistance mutations	[77–79]
	Dibenzoylmethane	Cells insensitive to p-eIF2α	Mechanism of action unclear	[80]
	Trazodone	Cells insensitive to p-eIF2α	Mechanism of action unclear	[80]
ISR activators
PERK	CCT020312	Enhances PERK activation	Mechanism of action unclear	[81]
	Tunicamycin	Induces ER stress: inhibits N-glycosylation	Activates all arms of the UPR	[82]
	Bortezomib	Induces ER stress: inhibits the proteasome	Pleotropic effects of proteasome inhibition	[83]
	Montelukast	Enhances PERK signalling Mechanism unclear	Leukotriene receptor antagonist	[84]
HRI	BTdCPU			[85]
	cHAUs			[86]
PKR	Interferon	Increases expression of PKR	Pleotropic effects of interferon signalling	[87]
	poly I:C	RNA mimetic	Requires transfection to enter cell	[88]
	BEPP	Mechanism of action unclear		[89]
GCN2	Histidinol	Inhibits histidinyl-tRNA synthetase		[90]
	Tryptophanol	Inhibits tryptophan-tRNA synthetase		[91]
	Halofuginone	Inhibits prolyl-tRNA synthetase		[92]
	L-asparaginase	Depletes extracellular asparagine		[93]
PPP1R15A	Salubrinal	Putative PPP1R15 inhibitor	Concerns that effects may be PPP1R15 independent	[67, 94]
	Guanabenz	Putative PPP1R15 inhibitor	Concerns that effects may be PPP1R15 independent	[67, 95, 96]
	Sephrin1	Putative PPP1R15 inhibitor	Concerns that effects may be PPP1R15 independent	[67, 97, 98]
PPP1R15A and B	Jasplakinolide	Depletes G-actin required for PPP1R15 function	Pleotropic effects of actin stabilisation	[99]

PERK: protein kinase R (PKR)-like endoplasmic reticulum kinase; HRI: heme-regulated inhibitor; GCN: general control nondepressible; eIF: eukaryotic initiation factor; 4-PBA: 4-phenylbutyric acid; ER: endoplasmic reticulum; UPR: unfolded protein response; TUDCA: tauroursodeoxycholic acid; C16: CAS 608512-97-6 [6,8-dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one]; C22: CAS 852547-30-9 (5-chloro-3-[(3,5-dichloro-4-hydroxyphenyl)methylidene]-2,3-dihydro-1H-indol-2-one); ISRIB: integrated stress response inhibitor [trans-2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetylamino)cyclohexyl)acetamide]; CCT020312: [6-bromo-3-[5-(4-bromo-phenyl)-1-(3-diethylamino-propionyl)-4,5-dihydro-1H-pyrazol-3-yl]-4-phenyl-1H-quinolin-2-one]; cHAUs: [1-((1,4-trans)-4-arylox-ycyclohexyl)-3-arylureas]; polyI:C: polyinosinic-polycytidylic acid; BEPP: [1H-benzimidazole-1-ethanol, 2,3-dihydro-2-imino-α-(phenoxymethyl)-3-(phenylmethyl)-monohydrochloride].