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A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders
The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-infl...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216254/ https://www.ncbi.nlm.nih.gov/pubmed/37238617 http://dx.doi.org/10.3390/biom13050747 |
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author | Kopp, Katherine O. Greer, Margaret E. Glotfelty, Elliot J. Hsueh, Shih-Chang Tweedie, David Kim, Dong Seok Reale, Marcella Vargesson, Neil Greig, Nigel H. |
author_facet | Kopp, Katherine O. Greer, Margaret E. Glotfelty, Elliot J. Hsueh, Shih-Chang Tweedie, David Kim, Dong Seok Reale, Marcella Vargesson, Neil Greig, Nigel H. |
author_sort | Kopp, Katherine O. |
collection | PubMed |
description | The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon’s normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions—in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer’s and Parkinson’s diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen’s disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component. |
format | Online Article Text |
id | pubmed-10216254 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102162542023-05-27 A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders Kopp, Katherine O. Greer, Margaret E. Glotfelty, Elliot J. Hsueh, Shih-Chang Tweedie, David Kim, Dong Seok Reale, Marcella Vargesson, Neil Greig, Nigel H. Biomolecules Review The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon’s normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions—in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer’s and Parkinson’s diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen’s disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component. MDPI 2023-04-26 /pmc/articles/PMC10216254/ /pubmed/37238617 http://dx.doi.org/10.3390/biom13050747 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Kopp, Katherine O. Greer, Margaret E. Glotfelty, Elliot J. Hsueh, Shih-Chang Tweedie, David Kim, Dong Seok Reale, Marcella Vargesson, Neil Greig, Nigel H. A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders |
title | A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders |
title_full | A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders |
title_fullStr | A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders |
title_full_unstemmed | A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders |
title_short | A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders |
title_sort | new generation of imids as treatments for neuroinflammatory and neurodegenerative disorders |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216254/ https://www.ncbi.nlm.nih.gov/pubmed/37238617 http://dx.doi.org/10.3390/biom13050747 |
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