Hypoxia‐Activated Prodrugs of PERK Inhibitors
Autor: | Dean C. Singleton, Lydia P. Liew, Stephen M. F. Jamieson, Michael P. Hay, Way W. Wong, Gary J. Cheng |
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Rok vydání: | 2019 |
Předmět: |
endocrine system
010402 general chemistry 01 natural sciences Biochemistry Structure-Activity Relationship eIF-2 Kinase chemistry.chemical_compound Tumor Cells Cultured medicine Humans Prodrugs PERK inhibitors Hypoxia Protein kinase A Protein Kinase Inhibitors Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Kinase Endoplasmic reticulum Organic Chemistry General Chemistry Prodrug Hypoxia (medical) HCT116 Cells 0104 chemical sciences Nitroimidazoles Drug Design Cancer research Unfolded protein response Growth inhibition medicine.symptom |
Zdroj: | Chemistry – An Asian Journal. 14:1238-1248 |
ISSN: | 1861-471X 1861-4728 |
Popis: | Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on-mechanism normal tissue toxicity. Hypoxia presents a target for tumour-selective drug delivery using hypoxia-activated prodrugs. We designed and prepared hypoxia-activated prodrugs of modified PERK inhibitors using a 2-nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction, or bioreduction in HCT116 cells, to release their effectors, albeit inefficiently. We examined the effects of the prodrugs on PERK signalling in hypoxic HCT116 cells. This study has identified a 2-substituted nitroimidazole carbamate prodrug with potential to deliver PERK inhibitors in a hypoxia-selective manner. |
Databáze: | OpenAIRE |
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