Non-teratogenic pomalidomide analog, 3-monothiopomalidomide inhibits nitrite and proinflammatory cytokines in vitro

Authors

• B Batsaikhan
• PH Parekh
• SC Hsueh
• D Tweedie
• BJ Hoffer
• N Vargesson
• DS Kim
• NH Greig

Abstract

Immunomodulatory imide drugs (IMiDs) provide a potential strategy to mitigate microglial-induced excessive neuroinflammation that commonly occurs in neurological disorders, particularly in neurodegenerative diseases. IMiDs, based on the backbone of thalidomide and pomalidomide (Pom), are anti-inflammatory and clinically efficacious in multiple myeloma but are compromised by their toxicity/teratogenicity. IMiD pharmacological actions are primarily mediated via interaction with cereblon (CRBN), a crucial component of the E3 ubiquitin ligase complex. IMiD-cereblon binding leads to the degradation of specific endogenous neosubstrates, such as SALL4 that is critical for embryo development. In pursuit of safer IMiDs, we synthesized a series of Pom analogs, and investigated their human CRBN binding activity, neosubstrate degradation, action on chicken embryo development, and evaluated their cell viability, oxidative stress and proinflammatory cytokine actions in lipopolysaccharide (LPS)-challenged immortal microglia (IMG) cells. Novel compound 3-monothiopomolidomide (3-MP) binds cereblon with high potency without lowering SALL4 or altering chicken embryo development (related to teratogenicity). Ex vivo evaluation demonstrated that 3-MP degrades Aiolos (related to immune modulation). IMG cells dose-dependently pretreated with 3-MP or Pom (0.6-60 µM) and, thereafter, challenged with LPS (30 ng/ml, 24 hr), retained cell viability (MTS assay) and demonstrated reductions in markers of oxidative stress (Griess nitrite assay) and pro-inflammatory cytokine levels (ELISA). These studies identified 3-MP as a new lead IMiD that suppresses inflammation but lacks human CRBN-mediated actions on SALL4, and provides a lead candidate for preclinical animal studies focused to mitigate neurodegeneration that involves a neuroinflammatory component, such as in traumatic brain injury, Alzheimer’s and Parkinson’s disease.

Scientific Focus Area: Neuroscience

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