{"title":"Synthesis and Biological Evaluation of Novel Anti-leukemia Proteolysis-Targeting Chimeras in Degradating Inosine Monophosphate Dehydrogenase.","authors":"Hamidreza Sohbati, Mohsen Amini, Saeed Balalaie","doi":"10.5812/ijpr-129251","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Proteolysis-targeting chimera (PROTAC) is a bifunctional molecule comprising a ligand to recognize the targeted protein to be degraded.</p><p><strong>Objectives: </strong>To use the advantages of the PROTAC technique, we have synthesized novel compounds to degrade inosine monophosphate dehydrogenase (IMPDH) by the proteasome system.</p><p><strong>Methods: </strong>We describe the synthesis of new PROTACs based on a combination of mycophenolic acid (MPA) as the potent IMPDH inhibitor and pomalidomide as a ligand of E3 ubiquitin ligase via linkers formed from Cu(I)-catalyzed cycloaddition reaction.</p><p><strong>Results: </strong>All synthesized compounds were investigated against Jurkat cells as acute T-cell leukemia and were potent apoptosis inducers at 50 nM.</p><p><strong>Conclusion: </strong>The effect of compound 2 in 0.05 μM on IMPDH degradation can be almost prevented by competition with bortezomib as the proteasome inhibitor at 0.1 and 0.5 μM.</p>","PeriodicalId":14595,"journal":{"name":"Iranian Journal of Pharmaceutical Research","volume":"21 1","pages":"e129251"},"PeriodicalIF":1.8000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6a/9e/ijpr-21-1-129251.PMC10024327.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Iranian Journal of Pharmaceutical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5812/ijpr-129251","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Proteolysis-targeting chimera (PROTAC) is a bifunctional molecule comprising a ligand to recognize the targeted protein to be degraded.
Objectives: To use the advantages of the PROTAC technique, we have synthesized novel compounds to degrade inosine monophosphate dehydrogenase (IMPDH) by the proteasome system.
Methods: We describe the synthesis of new PROTACs based on a combination of mycophenolic acid (MPA) as the potent IMPDH inhibitor and pomalidomide as a ligand of E3 ubiquitin ligase via linkers formed from Cu(I)-catalyzed cycloaddition reaction.
Results: All synthesized compounds were investigated against Jurkat cells as acute T-cell leukemia and were potent apoptosis inducers at 50 nM.
Conclusion: The effect of compound 2 in 0.05 μM on IMPDH degradation can be almost prevented by competition with bortezomib as the proteasome inhibitor at 0.1 and 0.5 μM.
期刊介绍：
The Iranian Journal of Pharmaceutical Research (IJPR) is a peer-reviewed multi-disciplinary pharmaceutical publication, scheduled to appear quarterly and serve as a means for scientific information exchange in the international pharmaceutical forum. Specific scientific topics of interest to the journal include, but are not limited to: pharmaceutics, industrial pharmacy, pharmacognosy, toxicology, medicinal chemistry, novel analytical methods for drug characterization, computational and modeling approaches to drug design, bio-medical experience, clinical investigation, rational drug prescribing, pharmacoeconomics, biotechnology, nanotechnology, biopharmaceutics and physical pharmacy.
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