Table 1.
Candidates to target UPR for cancer therapy
| Candidates | Molecular formula | Therapeutic effects associated with ER stress | Indications | References |
|---|---|---|---|---|
| Sunitinib | C22H27FN4O2 | Inhibits VEGFR and PDGFR, inhibits autophosphorylation and the subsequent IRE1α RNase activation | Renal cell carcinoma | [104-106] |
| B-I09 | C16H17NO5 | Inhibits endogenous IRE1α oligomerization, in vivo XBP1 mRNA cleavage and ER-localized mRNA decay | B cell chronic lymphocytic leukemia | [109] |
| STF-083010 | C15H11NO3S2 | Forms Schiff bases with Lys907and hydrogen bonds with Tyr892 in the IRE1 RNase structural domain | Multiple myeloma | [97,99] |
| 4μ8C | C11H8O4 | Forms Schiff bases with Lys907and hydrogen bonds with Tyr892 in the IRE1 RNase structural domain | Rheumatoid arthritis | [97,108,110,114] |
| Toyocamycin | C12H13N5O4 | Inhibits endogenous IRE1α oligomerization, in vivo XBP1 mRNA cleavage and ER-localized mRNA decay | Multiple myeloma | [97] |
| MKC-3946, | C21H20N2O3S | Inhibits endogenous IRE1α oligomerization, in vivo XBP1 mRNA cleavage and ER-localized mRNA decay | Multiple myeloma, triple-negative breast cancer, glioblastoma multiforme | [97,109,115] |
| MKC-8866 | C18H19NO7 | |||
| Methotrexate | C20H22N8O5 | Inhibits IRE1 RNase activity | Glioblastoma multiforme | [120] |
| Cefoperazone | C25H27N9O8S2 | Inhibits IRE1 RNase activity | Glioblastoma multiforme | [120] |
| Folinic acid | C20H23N7O7 | Inhibits IRE1 RNase activity | Glioblastoma multiforme | [120] |
| Fludarabine phosphate | C10H13FN5O7P | Inhibits IRE1 RNase activity | Glioblastoma multiforme | [120] |
| GSK2606414, | C24H20F3N5O | Inhibits PERK, inhibits eIF2α phosphorylation (or not), ATF4 translation and CHOP mRNA expression | Hypothalamic neuronal injury, bone loss, multiple myeloma, pancreatic adenocarcinoma | [98,122,123,125] |
| GSK2656157 | C23H21FN6O | |||
| Sal003 | C18H15Cl4N3OS | Blocks eIF2α phosphatase activity | Glioblastoma multiforme | [126,127] |
| ISRIB | C22H24Cl2N2O4 | Releases eIF2α phosphorylation-mediated inhibition of protein translation | Prostate cancer | [129,130] |
| AMG’44 | C34H29ClN4O2 | Inhibits PERK | / | [131] |
| EGCG | C22H18O11 | Binds to the ATP-binding structural domain of GRP78 and block its function | Breast cancer, prostate cancer | [133-135] |
| PHOS | C21H31KO6S | Inhibits GRP78 activity | Colorectal cancer | [136] |
| KP1339/IT-139 | C14H12Cl4N4NaRu | Depletes GRP78 and disrupts ER homeostasis specifically | Colorectal cancer | [137] |
| HA15 | C23H22N4O3S2 | Inhibits ATPase activity | Melanoma, breast cancer, pancreatic cancer, adrenocortical carcer, lung cancer | [138-140] |