Introduction
The unfolded protein response
PERK-eIF2α
ATF6α
IRE-1α—XBP1/RIDD
Role of the UPR in AML
UPR and C/EBPα in AML
UPR and PML-RARα in AML
UPR and hypoxia in AML
Role of the UPR in B-ALL
UPR and BCR-ABL1 in B-ALL
UPR and stem cells
The UPR as a druggable target
Concept of proteotoxicity as a therapeutic approach
Targeting PERK
Targeting GRP78
Compound | Molecular target | Disease | Stage of clinical development | References |
---|---|---|---|---|
Epigallocatechin gallate (EGCG) | GRP78 | Alzheimer’s disease | Clinical, phase 2 and 3 | NCT00951834 |
PAT-SM6 | GRP78 | Multiple myeloma | Clinical, phase 1 | NCT01727778, Rasche et al. [115] |
Targeting IRE-1α/XBP1s signaling
Compound | Molecular target | Disease | Stage of clinical development | References |
---|---|---|---|---|
STF-083010 | IRE-1 | Multiple myeloma | Preclinical | Papandreou et al. [99] |
ALL | Kharabi Masouleh et al. [87] | |||
CLL | Kriss et al. [116] | |||
A106 | IRE-1 | CLL | Preclinical | Kriss et al. [116] |
ALL | Kharabi Masouleh et al. [87] | |||
MKC-3946 | IRE-1 | Multiple myeloma | Preclinical | Volkmann et al. [100] |
Mimura et al. [101] | ||||
4μ8c | IRE-1 | Multiple myeloma | Preclinical | Cross et al. [102] |
GSK2606414 | PERK | Multiple myeloma | Preclinical | Axten et al. [98] |
GSK2656157 | Pancreatic cancer | |||
Epigallocatechin gallate (EGCG) | GRP78 | ALL | Preclinical | Uckun et al. [111] |
PAT-SM6 | GRP78 | Melanoma | Preclinical | Rosenez et al. [113] |
Multiple myeloma | Rasche et al. [114] | |||
Pep42 | GRP78 | ALL | Preclinical | Uckun et al. [111] |