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Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies. The small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling. ALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1β, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics. Targeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD. [Display omitted] • Novel compound ALD-R491 specifically binds to vimentin with no off-target effects. • ALD-R491 is significantly more effective than 5-ASA and Tofacitinib in DSS model. • ALD-R491 blocks the onset and progression of spontaneous colitis in IL-10 KO mice. • ALD-R491 impacts Th17/Treg, intestinal barrier, tissue fibrosis and gut microbiome. • Targeting vimentin by ALD-R491 represents a first-in-class MOA in treating IBD. [ABSTRACT FROM AUTHOR]

Herein, we describe the design, synthesis and structure−activity relationships of a series of novel s-triazine compounds can induce methuotic phenotype in various types of cancer cells. (E)-1-(4-Chlorophenyl)-3-(4-((4-morpholino-6-styryl-1,3,5-triazine-2-yl)amino)phenyl)urea, compound V6 , exhibited a striking methuotic phenotype with a minimal effective concentration of less than 10 nM in U87 glioblastoma cells. Based on structure−activity relationship studies, we designed and synthesized an active probe P1 that retained the full potential of V6 in inducing the methuotic phenotype in U87 glioblastoma cells. Using this probe following affinity-based proteomic profiling strategy, we identified vimentin as the specific target protein of compound V6. Molecular docking revealed that V6 can form hydrogen bonds with vimentin at 273R and 276Y in its rod domain. Image 1 • Design and synthesis of a series of novel s-triazine compounds inducing methuotic phenotype are reported. • Compound V6 exhibited a striking methuotic phenotype with <10 nM in U87 glioblastoma cells. • Probe (P1) of the most interesting compound V6 was designed and synthesized. • Vimentin was identified as the specific target protein of V6 following affinity-based proteomic profiling strategy. [ABSTRACT FROM AUTHOR]