Apratastat

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)