immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial antiinflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs.
Methods: TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions.
Results: TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 hr post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice.
Conclusion: TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity53 associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurodegenerative disorders involving a neuroinflammatory component.
Bibliographical noteThe authors acknowledge support from their associated institutions which included (i) the Intramural Research Program, National Institute on Aging, NIH, USA, (ii) Aevis Bio Inc., S. Korea, (iii) Aevisbio Inc., USA; (iv) Aga Khan University, Pakistan; (v) University of Aberdeen, Scotland, UK; (vi) Case Western Reserve University School of Medicine, Cleveland, USA; (vii) Taipei Medical University, Taiwan.
This research was supported in part by: (i) The Intramural Research Program, National Institute on Aging, National Institutes of Health, USA, (AG000994), (ii) National Institutes of Health grant R56 AG057028, USA, (iii) the Technology Development Program of MSS (S2782046) and the National Research Foundation (NRF) grant funded by the Korean government (2021M3A9G2015889), and (iv) the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program Grants, (v) the Sunny Brain Tumor and Brain Disease Research and Development Fund (106-5310-001-400), (vi) TMU-CWRU(CTSC) Pilot Program (107-3805-004-400), and (vii) the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-038-106).
Data Availability StatementData is available from the corresponding authors on request.
- Immunomodulatory imide drugs 60 (IMiDs)
- Spalt Like Transcription Factor (SALL4)