Table 2.
PERK pathway modulators.
| Modulators (Compounds) | PERK Pathway Outcome | Neurodegenerative Diseases | Additional Targets |
|---|---|---|---|
| MK-28 | Activation (via activating PERK) |
HD [87] | |
| CCT020312 | Activation (Nrf2 branch) |
PSP [129] | |
| GSK260414 | Inhibition (via inhibiting PERK) |
Prion Disease [130], PD [131], FD [132], AD [133] | RIPK1 [134] |
| GSK2656157 | Traumatic brain injury [135] |
||
| Echinacoside (ECH) | AD [136,137], PD [138] | Ghrelin receptor [139], Androgen receptor [140] |
|
| SC79 | Inhibition (activates AKT causing inhibitory phosphorylation of PERK kinase loop) |
Prion Disease [141] | |
| 2BAct | Inhibition (downstream of P-eIF2α, via eIF2B activation) |
VWMD [58] | |
| ISRIB | ALS [142], VWMD [59], AD [143], TBI [144] | ||
| Dibenzoylmethane (DBM) |
Inhibition (downstream of P-eIF2α, similar activity to that of ISRIB) |
FTD [145], Prion disease [145], PD [146] | Nrf2 [147], AMPK [148] |
| Trazodone HCl | T-type calcium channel [149], monoamine receptor [150] | ||
| Guanabenz | Activation (via inhibiting dephosphorylation of P-eIF2α, inhibits GADD34) |
VWMD [117], ALS [116], PD [118,120] | ASICs [151] |
| PromISR-6 (guanabenz analog, target unknown) |
HD [127] | Possibly activator of PERK and other eIF2α kinases [127] | |
| Salubrinal | PD [53,56,114], TBI [113], HD [79] | CReP inhibitor, Dusp2 (PAC1) inhibitor [152] | |
| Sephin1 | ALS [123], Charcot-Marie-Tooth disease [123], MS [124], Prion Disease [125] | ASICs [151] | |
| Raphin1 | Activation (via inhibiting dephosphorylation of P-eIF2α, inhibits CReP) |
HD [128] | |
| Bruceine D | Activation (Nrf2 branch, mechanism unknown) |
PD [153] | Notch [154], JNK [155] |
| Naringenin (NAR) | PD [156], AD [157,158] | CRMP-2 [158] | |
| Sulforaphane (SFN) | Activation (Nrf2 branch—acts on KEAP1, releasing Nrf2) |
PD [159,160,161], HD [162], AD [163,164,165,166], MS [167], FRDA [168] | BACE1 [169], NF-κB [170] |
| Tertbuthyl-hydroquinene (tBHQ) | Activation (Nrf2 branch) |
HD [171], AD [172], PD [173] | |
| Acetylenic tricyclic bis(cyanoenone) TBE-31 | Activation (Nrf2 branch—binds KEAP1, thus releasing Nrf2) |
FRDA [168] | |
| RTA-408 (omaveloxolone) |
FRDA [174] | ||
| Dimethylfumarate (DFM) | MS [175], PD [176,177] | MSK1 and RSK1 [178,179] and others [180] |