TMI-1 (WAY-171318), a novel orally active inhibitor of ADAM17 (TACE) and MMP, induces tumor apoptosis in a breast cancer.

MMP2:4.7 nM, TNF-α secretion (THP-1 cells):200 nM, MMP9:12 nM, ADAM17/TACE:0.079 nM(ki), MMP14:26 nM, MMP13:3 nM, ADAMTS-4:100 nM, ADAM10:16 nM(ki), MMP7:26 nM, ADAM17/TACE:8.4 nM (IC50), TNF-α secretion (Raw cells):40 nM, MMP1:6.6 nM, ADAM8:21 nM(ki), ADAM12:1.8 nM(ki)

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.[3]

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]