Targeting neuroinflammation: 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration

Shih-Chang  Hsueh; Pathik  Parekh; Buyandelger  Batsaikhan; Neil Vargesson; David Tweedie; Weiming  Luo; Chirag N.  Patel; Dong  Liu; Ross A.  McDevitt; Abdul Mannan  Baig; Yu Kyung  Kim; Sun  Kim; Inho  Hwang; Juwan  Kim; Mee Youn  Lee; Anna R.  Carta; Warren R.  Selman; Barry J.  Hoffer; Dong Seok  Kim; Nigel H Greig

doi:10.1186/s12929-025-01150-w

Targeting neuroinflammation: 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration

Shih-Chang Hsueh^* (Corresponding Author), Pathik Parekh^* (Corresponding Author), Buyandelger Batsaikhan, Neil Vargesson, David Tweedie, Weiming Luo, Chirag N. Patel, Dong Liu, Ross A. McDevitt, Abdul Mannan Baig, Yu Kyung Kim, Sun Kim, Inho Hwang, Juwan Kim, Mee Youn Lee, Anna R. Carta, Warren R. Selman, Barry J. Hoffer, Dong Seok Kim, Nigel H Greig

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Backgound: Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation.
Methods: 3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised.
Results: 3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces proinflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers proinflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory 1L-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44-0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI.
Conclusion: 3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.

Original language	English
Article number	57
Number of pages	29
Journal	Journal of Biomedical Science
Volume	32
Early online date	16 Jun 2025
DOIs	https://doi.org/10.1186/s12929-025-01150-w
Publication status	Published - 2025

Bibliographical note

All authors thank Dr. Michael T. Scerba (Intramural Research Program, National Institute on Aging, NIH, USA) for quantifying the concentration of 3-MP following its nanoformulation.

Data Availability Statement

All data and materials are available on reasonable request to the authors.

Funding

All authors acknowledge support from their associated institutions which included (i) the Intramural Research Program, National Institute on Aging, NIH, USA (AG 000994); (ii) Marcus Neuroscience Institute Philanthropic Fund, USA; (iii) Aevis Bio, Inc., Republic of Korea (the Korea Dementia Research Center 31 (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (RS-2024-0034124913), the Korea Drug Development Fund funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare, Republic of Korea (KDDF RS2024-00338017)), (iv) Aevisbio, Inc., USA.

Funders	Funder number
Ministry of Health & Welfare	RS-2024-0034124913, KDDF RS2024-00338017

Keywords

Neuroinflammation
Immunomodulatory imide drugs (IMiDs)
Meurodegeneration
Microglia
Tetratogenicity
Pomalidomide
cereblon
Splat like transcription factor
SALL4
Traumatic brain injury

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Hsueh, S.-C., Parekh, P., Batsaikhan, B., Vargesson, N., Tweedie, D., Luo, W., Patel, C. N., Liu, D., McDevitt, R. A., Baig, A. M., Kim, Y. K., Kim, S., Hwang, I., Kim, J., Lee, M. Y., Carta, A. R., Selman, W. R., Hoffer, B. J., Kim, D. S., & Greig, N. H. (2025). Targeting neuroinflammation: 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration. Journal of Biomedical Science, 32, Article 57. https://doi.org/10.1186/s12929-025-01150-w

Hsueh, S-C, Parekh, P, Batsaikhan, B, Vargesson, N, Tweedie, D, Luo, W, Patel, CN, Liu, D, McDevitt, RA, Baig, AM, Kim, YK, Kim, S, Hwang, I, Kim, J, Lee, MY, Carta, AR, Selman, WR, Hoffer, BJ, Kim, DS & Greig, NH 2025, 'Targeting neuroinflammation: 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration', Journal of Biomedical Science, vol. 32, 57. https://doi.org/10.1186/s12929-025-01150-w

@article{40e50eca242849059779adbd9e141508,

title = "Targeting neuroinflammation: 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration",

abstract = "Backgound: Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson{\textquoteright}s disease (PD) and Alzheimer{\textquoteright}s disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation.Methods: 3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised.Results: 3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces proinflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers proinflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory 1L-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44-0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI.Conclusion: 3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.",

keywords = "Neuroinflammation, Immunomodulatory imide drugs (IMiDs), Meurodegeneration, Microglia, Tetratogenicity, Pomalidomide, cereblon, Splat like transcription factor, SALL4, Traumatic brain injury",

author = "Shih-Chang Hsueh and Pathik Parekh and Buyandelger Batsaikhan and Neil Vargesson and David Tweedie and Weiming Luo and Patel, {Chirag N.} and Dong Liu and McDevitt, {Ross A.} and Baig, {Abdul Mannan} and Kim, {Yu Kyung} and Sun Kim and Inho Hwang and Juwan Kim and Lee, {Mee Youn} and Carta, {Anna R.} and Selman, {Warren R.} and Hoffer, {Barry J.} and Kim, {Dong Seok} and Greig, {Nigel H}",

note = "All authors thank Dr. Michael T. Scerba (Intramural Research Program, National Institute on Aging, NIH, USA) for quantifying the concentration of 3-MP following its nanoformulation. ",

year = "2025",

doi = "10.1186/s12929-025-01150-w",

language = "English",

volume = "32",

journal = "Journal of Biomedical Science",

issn = "1423-0127",

publisher = "BMC",

}

TY - JOUR

T1 - Targeting neuroinflammation

T2 - 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration

AU - Hsueh, Shih-Chang

AU - Parekh, Pathik

AU - Batsaikhan, Buyandelger

AU - Vargesson, Neil

AU - Tweedie, David

AU - Luo, Weiming

AU - Patel, Chirag N.

AU - Liu, Dong

AU - McDevitt, Ross A.

AU - Baig, Abdul Mannan

AU - Kim, Yu Kyung

AU - Kim, Sun

AU - Hwang, Inho

AU - Kim, Juwan

AU - Lee, Mee Youn

AU - Carta, Anna R.

AU - Selman, Warren R.

AU - Hoffer, Barry J.

AU - Kim, Dong Seok

AU - Greig, Nigel H

N1 - All authors thank Dr. Michael T. Scerba (Intramural Research Program, National Institute on Aging, NIH, USA) for quantifying the concentration of 3-MP following its nanoformulation.

PY - 2025

Y1 - 2025

N2 - Backgound: Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation.Methods: 3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised.Results: 3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces proinflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers proinflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory 1L-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44-0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI.Conclusion: 3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.

AB - Backgound: Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation.Methods: 3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised.Results: 3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces proinflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers proinflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory 1L-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44-0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI.Conclusion: 3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.

KW - Neuroinflammation

KW - Immunomodulatory imide drugs (IMiDs)

KW - Meurodegeneration

KW - Microglia

KW - Tetratogenicity

KW - Pomalidomide

KW - cereblon

KW - Splat like transcription factor

KW - SALL4

KW - Traumatic brain injury

U2 - 10.1186/s12929-025-01150-w

DO - 10.1186/s12929-025-01150-w

M3 - Article

SN - 1423-0127

VL - 32

JO - Journal of Biomedical Science

JF - Journal of Biomedical Science

M1 - 57

ER -

Targeting neuroinflammation: 3-Monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration

Abstract

Bibliographical note

Data Availability Statement

Funding

Keywords

UN SDGs

Access to Document

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Cite this