An inhibitor of ADAM17 and MMPs
TMI-005 is an inhibitor of disintegrin and metalloproteinase domain-containing protein 17/TNF-α converting enzyme (ADAM17/TACE), matrix metalloproteinase-1 (MMP-1), and MMP-13 (IC50s = 20, 33, and 8.1 nM, respectively).1 It inhibits LPS-induced TNF-α release in isolated human whole blood (IC50 = 144 ng/ml).2 TMI-005 (25 μM) reduces basal and ionizing radiation-induced secretion of the ADAM17/TACE substrates ALCAM and amphiregulin from A549 and NCI H125 cells.3 It inhibits proliferation of A549 cells when used at concentrations of 25 and 50 μM and sensitizes A549 and NCI H125 cells to ionizing radiation at 25 μM. TMI-005 (25 mg/kg twice per day) reduces tumor growth in an A549 mouse xenograft model when administered in combination with ionizing radiation.
1.Levin, J.I., Chen, J.M., and Cole, D.C.Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitorsWO 00/44709(2000) 2.Shu, C., Zhou, H., Afsharvand, M., et al.Pharmacokinetic-pharmacodynamic modeling of apratastat: A population-based approachJ. Clin. Pharmacol.51(4)472-481(2011) 3.Sharma, A., Bender, S., Zimmerman, M., et al.Secretome signature identifies ADAM17 as novel target for radiosensitization of non-small cell lung cancerClin. Cancer Res.22(17)4428-4439(2016)
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