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

Katherine O. Kopp, Margaret E. Greer, Elliot J. Glotfelty, Shih-Chang Hsueh, David Tweedie, Dong Seok Kim, Marcella Reale, Neil Vargesson, Nigel H Greig* (Corresponding Author)

*Corresponding author for this work

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Abstract

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 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.
Original languageEnglish
Article number747
Number of pages34
JournalBiomolecules
Volume13
Issue number5
Early online date26 Apr 2023
DOIs
Publication statusPublished - 26 Apr 2023

Bibliographical note

Acknowledgements
The authors acknowledge support from their associated institutions which included: (i) the Intramural Research Program, National Institute on Aging, NIH, USA, (ii) the Karolinska Institutet, Sweden, (iii) Aevisbio Inc., USA, (iv) Aevis Bio Inc., Republic of Korea, (v) G. d’Annunzio University of Chieti and Pescara, Italy, and (vi) University of Aberdeen, Scotland,
UK.
Funding
The generation of this article was supported by: (i) the Intramural Research Program, National Institute on Aging, NIH: AG000994. (ii) The Technology Development Program of MSS, Republic of Korea (S2782046). (iii) The National Research Foundation (NRF) grant funded by the Republic of Korea Government (2021M3A9G2015889).

Keywords

  • Immunomodulatory imide drugs (IMiDs)
  • thalidomide
  • pomalidomide
  • neuroinflammation
  • cereblon
  • traumatic brain injury;
  • Alzheimer’s disease
  • Parkinson’s disease
  • neurodegeneration
  • erythema nodosum leprosum

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