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] |