{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:54:40Z","timestamp":1787313280253,"version":"build-2736575974"},"reference-count":154,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Intramural Research Program, National Institute on Aging, NIH","award":["AG000994"],"award-info":[{"award-number":["AG000994"]}]},{"name":"the Intramural Research Program, National Institute on Aging, NIH","award":["S2782046"],"award-info":[{"award-number":["S2782046"]}]},{"name":"the Intramural Research Program, National Institute on Aging, NIH","award":["2021M3A9G2015889"],"award-info":[{"award-number":["2021M3A9G2015889"]}]},{"name":"the Intramural Research Program, National Institute on Aging, NIH","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}]},{"name":"The Technology Development Program of MSS, Republic of Korea","award":["AG000994"],"award-info":[{"award-number":["AG000994"]}]},{"name":"The Technology Development Program of MSS, Republic of Korea","award":["S2782046"],"award-info":[{"award-number":["S2782046"]}]},{"name":"The Technology Development Program of MSS, Republic of Korea","award":["2021M3A9G2015889"],"award-info":[{"award-number":["2021M3A9G2015889"]}]},{"name":"The Technology Development Program of MSS, Republic of Korea","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}]},{"name":"The National Research Foundation (NRF) grant funded by the Republic of Korea Government","award":["AG000994"],"award-info":[{"award-number":["AG000994"]}]},{"name":"The National Research Foundation (NRF) grant funded by the Republic of Korea Government","award":["S2782046"],"award-info":[{"award-number":["S2782046"]}]},{"name":"The National Research Foundation (NRF) grant funded by the Republic of Korea Government","award":["2021M3A9G2015889"],"award-info":[{"award-number":["2021M3A9G2015889"]}]},{"name":"The National Research Foundation (NRF) grant funded by the Republic of Korea Government","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}]},{"name":"The Italian Ministry of Education, University and Research. University \u201cG. d\u2019Annunzio\u201d","award":["AG000994"],"award-info":[{"award-number":["AG000994"]}]},{"name":"The Italian Ministry of Education, University and Research. University \u201cG. d\u2019Annunzio\u201d","award":["S2782046"],"award-info":[{"award-number":["S2782046"]}]},{"name":"The Italian Ministry of Education, University and Research. University \u201cG. d\u2019Annunzio\u201d","award":["2021M3A9G2015889"],"award-info":[{"award-number":["2021M3A9G2015889"]}]},{"name":"The Italian Ministry of Education, University and Research. University \u201cG. d\u2019Annunzio\u201d","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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\u2019s normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions\u2014in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-\u03b1 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\u2019s and Parkinson\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/biom13050747","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T02:30:52Z","timestamp":1682476252000},"page":"747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3011-8854","authenticated-orcid":false,"given":"Katherine O.","family":"Kopp","sequence":"first","affiliation":[{"name":"Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, Biomedical Research Center, 251 Bayview Blvd., NIH, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret E.","family":"Greer","sequence":"additional","affiliation":[{"name":"Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, Biomedical Research Center, 251 Bayview Blvd., NIH, Baltimore, MD 21224, USA"},{"name":"Faculty of Medicine, Georgetown University School of Medicine, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5125-8720","authenticated-orcid":false,"given":"Elliot J.","family":"Glotfelty","sequence":"additional","affiliation":[{"name":"Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, Biomedical Research Center, 251 Bayview Blvd., NIH, Baltimore, MD 21224, USA"},{"name":"Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Chang","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, Biomedical Research Center, 251 Bayview Blvd., NIH, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Tweedie","sequence":"additional","affiliation":[{"name":"Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, Biomedical Research Center, 251 Bayview Blvd., NIH, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8837-8822","authenticated-orcid":false,"given":"Dong Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"Aevisbio Inc., Gaithersburg, MD 20878, USA"},{"name":"Aevis Bio Inc., Daejeon 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4164-8781","authenticated-orcid":false,"given":"Marcella","family":"Reale","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, G. d\u2019Annunzio University of Chieti and Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8027-114X","authenticated-orcid":false,"given":"Neil","family":"Vargesson","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-1468","authenticated-orcid":false,"given":"Nigel H.","family":"Greig","sequence":"additional","affiliation":[{"name":"Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, Biomedical Research Center, 251 Bayview Blvd., NIH, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"541","DOI":"10.2174\/1381612822666151125000300","article-title":"Inflammatory Process in Alzheimer\u2019s and Parkinson\u2019s Diseases: Central Role of Cytokines","volume":"22","author":"Alam","year":"2016","journal-title":"Curr. 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