TMI 1

TMI 1 is an inhibitor of disintegrin and metalloproteinase domain-containing protein 17 (ADAM17/TACE; IC50 = 8.4 nM in a cell-free enzyme assay).1 It inhibits matrix metalloproteinase-1 (MMP-1), -2, -7, -9, -13, and -14, as well as ADAM-TS-4 in vitro (IC50s = 6.6, 4.7, 26, 12, 3, 26, and 100 nM, respectively). It also inhibits ADAM8, -10, -12, and -17/TACE in cell-free enzyme assays with Ki values of 21, 16, 1.8, and 0.079 nM, respectively, with slow-binding inhibition of ADAM17/TACE but not the other ADAM enzymes.2 TMI 1 inhibits LPS-induced TNF-α secretion in Raw and THP-1 cells (IC50s = 40 and 200 nM, respectively), as well as in isolated human monocytes and whole blood (IC50s = 190 and 300 nM, respectively).1 It inhibits the production of TNF-α ex vivo in synovium isolated from the inflamed joints of patients with rheumatoid arthritis with IC50 values of less than 100 nM without inhibiting TNF-α expression in vitro. TMI 1 inhibits LPS-induced TNF-α production in mice (ED50 = 5 mg/kg) and reduces disease severity in mouse models of collagen-induced arthritis. It also decreases cell viability of (ED50s = 1.3-8.1 μM), and induces caspase-3/7 activity in, a variety of cancer cell lines and induces tumor apoptosis and reduces tumor growth in an MMTV-ErbB2/neu mouse model of breast cancer when administered at a dose of 100 mg/kg.3

|1. Zhang, Y., Xu, J., Levin, J., 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-α-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J. Pharmacol. Exp. Ther. 309(1), 348-355 (2004).|2. Moss, M.L., and Rasmussen, F.H. Fluorescent substrates for the proteinases ADAM17, ADAM10, ADAM8, and ADAM12 useful for high-throughput inhibitor screening. Anal. Biochem. 366(2), 144-148 (2007).|3. Mezil, L., Berruyer-Pouyet, C., Cabaud, O., et al. Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1) in breast cancer. PLoS One 7(9), e43409 (2012).