TMI 1 Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
TMI 1 is an inhibitor of disintegrin and metalloproteinase domain-containing protein 17 (ADAM17/TACE; IC
50 = 8.4 nM in a cell-free enzyme assay). It inhibits matrix metalloproteinase-1 (MMP-1), -2, -7, -9, -13, and -14, as well as ADAM-TS-4
in vitro (IC
50s = 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 K
i values of 21, 16, 1.8, and 0.079 nM, respectively, with slow-binding inhibition of ADAM17/TACE but not the other ADAM enzymes. TMI 1 inhibits LPS-induced TNF-α secretion in Raw and THP-1 cells (IC
50s = 40 and 200 nM, respectively), as well as in isolated human monocytes and whole blood (IC
50s = 190 and 300 nM, respectively). It inhibits the production of TNF-α
ex vivo in synovium isolated from the inflamed joints of patients with rheumatoid arthritis with IC
50 values of less than 100 nM without inhibiting TNF-α expression
in vitro. TMI 1 inhibits LPS-induced TNF-α production in mice (ED
50 = 5 mg/kg) and reduces disease severity in mouse models of collagen-induced arthritis. It also decreases cell viability of (ED
50s = 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.
Verwenden
TMI 1 is a dual TACE/MMP inhibitor, which represents a unique class of orally bioavailable small molecule TNF inhibitors that may be effective and beneficial for treating rhuematoid arthritis.
TMI 1 Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
