MedChemExpress LLC (MCE)

MedChemExpress - Model TMI-1 - 287403-39-8

TMI-1 (WAY-171318) inhibits TNF converting enzyme (TACE) (IC50 of 8.4 nM), ADAM-TS-4, ADAM-17 and various MMPs with oral activity. TMI-1 significantly suppresses the secretion of TNF-α , alleviating collagen-induced arthritis in mice. TMI-1 inhibits cancer cell proliferation, induces apoptosis through a caspase-dependent pathway. TMI-1 also reverses TRPV1 upregulation and lowers the levels of inflammatory factors (TNF-α、IL-1β、IL-6) in nerve cells, protecting against paclitaxel-induced neurotoxicity. TMI-1 leads to changes in pro-atherogenic lipoprotein profiles, but does not affect the progression of early lesions[1][2][3][4].

TMI-1

MCE China：TMI-1

Brand：MedChemExpress (MCE)

Cat. No.HY-101448

CAS：287403-39-8

Synonyms：WAY-171318

Purity：99.59%

Storage：Powder -20°C 3 years In solvent -80°C 6 months -20°C 1 month

Shipping：Room temperature in continental US; may vary elsewhere.

Description：TMI-1 (WAY-171318) inhibits TNF converting enzyme (TACE) (IC50 of 8.4 nM), ADAM-TS-4, ADAM-17 and various MMPs with oral activity. TMI-1 significantly suppresses the secretion of TNF-α , alleviating collagen-induced arthritis in mice. TMI-1 inhibits cancer cell proliferation, induces apoptosis through a caspase-dependent pathway. TMI-1 also reverses TRPV1 upregulation and lowers the levels of inflammatory factors (TNF-α、IL-1β、IL-6) in nerve cells, protecting against paclitaxel-induced neurotoxicity. TMI-1 leads to changes in pro-atherogenic lipoprotein profiles, but does not affect the progression of early lesions.

In Vitro：TMI-1 inhibits TNF-α secretion in mouse monocyte Raw cells with an IC50 of 40 nM, in human monocyte THP-1 cells with an IC50 of 200 nM, in primary human monocyte lines with an IC50 of 190 nM, and in human whole blood with an IC50 of 300 nM[1]. TMI-1 inhibits the shedding of TNFR II in human whole blood, with an IC50 of 0.72μM[1]. TMI-1 (0-20 μM, 5 days) shows a dose-dependent inhibition of proliferation in breast cancer cell lines BT-20, SUM149, MDA-MB-231, SK-BR-3, L226, SUM190, T147D and Cama-1, with ED50 of 1.3, 1.5, 8.1, 1.6, 2.0, 2.0, 2.5, and 2.5 μM respectively, and induces the activity of Caspase-3 and Caspase-7 without affecting the vitality of normal cells[2]. TMI-1 (0-20 μM, 48 h) inhibits the cell cycle of breast cancer cells SUM149, promotes apoptosis, activates Caspase-3, Caspase-7, Caspase-8, Caspase-9, and increases ROS production[2]. TMI-1 (4 ng/mL, 24 h) improves the degenerative changes in the axons of 50B11 cells induced by paclitaxel (HY-B0015) and enhances the growth of neurites induced by forskolin (HY-15371), and this effect is dose-dependent[3]. TMI-1 (0.04-4 ng/mL, 24 h) reduces the expression of TRPV1 protein in 50B11 cells in a dose-dependent manner, along with a decrease in the expressions of PKC, PI3K, NF-κB, TNF-α, IL-1β, and IL-6 mRNA, as well as calcium influx[3].

In Vivo：TMI-1 (0-50 mg/kg, twice a day, 14-17 days, oral) is effective in both therapeutic and preventive arthritis mouse models, reducing disease severity[1]. TMI-1 (100 mg/kg, daily, 30 days, oral) slows down breast cancer tumor growth and prevents tumor occurrence in a breast cancer mouse model[2]. TMI-1 (100 mg/kg, daily, 4 weeks, oral) alters the lipoprotein profile that promotes atherosclerosis but does not affect the progression of early atherosclerotic lesions[4]. Analysis of pharmacokinetics in Balb/CJ mice after a single oral dose of 50 mg/kg[1] Route Dose (mg/kg) AUC (ng•h/mL) bioavailability (%) t1/2 (h) Cmax (μM) oral 50 1484 39 1.68 3

IC50 & Target：IL-6 IL-1β MMP-1 6.6 nM (IC50) MMP-2 4.7 nM (IC50) MMP-7 26 nM (IC50) MMP-14 26 nM (IC50) MMP-9 12 nM (IC50) MMP-13 3 nM (IC50) TACE 8.8 nM (IC50) ADAM17 ADAM-TS-4 100 nM (IC50)

References：

[1]. Zhang Y, et al. Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a novel dual tumor necrosis factor-alpha-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J Pharmacol Exp Ther. 2004 Apr;309(1):348-55. [Content Brief]

[2]. Mezil L, et al. Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1) in breast cancer. PLoS One. 2012;7(9):e43409. [Content Brief]

[3]. Yesul Kim, et al. TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro. Front Pharmacol. 2022 Feb 16:13:842779. [Content Brief]

[4]. Wynand Melenhorst, et al. ADAM17 INHIBITION IN APOE DEFICIENT MICE RESULTS IN A PROATHEROGENIC LIPOPROTEIN PROFILE WITHOUT AFFECTING ATHEROSCLEROSIS. University of Groningen.

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