A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders

作者：Katherine O. Kopp, Margaret E. Greer, Elliot J. Glotfelty, Shih‐Chang Hsueh, David Tweedie, Dong Seok Kim, Marcella Reale, Neil Vargesson, Nigel H. Greig · 发表于：Biomolecules · 年份：2023 · DOI：10.3390/biom13050747 · 被引用次数：23 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Histone Deacetylase Inhibitors Research

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...