Description
Ilomastat (142880-36-2) is a potent pan-specific inhibitor of matrix metalloproteinases (MMPs).1 Ki values have been reported for the following human MMPs: MMP-1, 0.4nM; MMP-2, 0.5nM; MMP-3, 27nM; MMP-7, 3.7nM; MMP-8, 0.1nM; MMP-9, 0.2nM; MMP-12, 3.6nM; MMP-14, 13.4nM; MMP-26, 0.36nM.2-4 Also inhibits MMP-10, MMP-13, MMP-15, MMP-17, MMP-20, MMP-21, TACE and ADAM19.
Uses
GM 6001 is a potent, reversible broad spectrum inhibitor of zinc-containing proteases, including matrix metalloproteinases (MMPs). It inhibits zinc-containing thermolysin and elastase from P. aeruginosa, both with Ki values of 20 nM. GM 6001 inhibits MMP-1, -2, -7, -8, -9, -12, -13, -14, -16, and -26 with Ki or IC50 values between 0.1 and 10 nM. It inhibits disintegrin and metalloproteinase domain-containing (ADAM) proteins ADAM9, ADAM10, ADAM12, and ADAM17 at nanomolar concentrations. It less potently inhibits lethal factor from B. anthracis anthrax lethal toxin (Ki = 2.74 μM). GM 6001 also impairs the growth of the human pathogen Chlamydia by inhibiting peptide deformylase, which contains iron rather than zinc (IC50 = 38 nM).
Definition
ChEBI: Ilomastat is an N-acyl-amino acid obtained by formal condensation of the carboxy group of (2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoic acid with the amino group of N-methyl-L-tryptophanamide. A cell permeable broad-spectrum matrix metalloproteinase (MMP) inhibitor It has a role as an EC 3.4.24.24 (gelatinase A) inhibitor, a neuroprotective agent, an anti-inflammatory agent, an antibacterial agent and an antineoplastic agent. It is a L-tryptophan derivative, a hydroxamic acid and a N-acyl-amino acid.
General Description
A cell-permeable, potent broad-spectrum hydroxamic acid inhibitor of matrix metalloproteinases (MMPs). [Ki = 0.4 nM for skin fibroblast collagenase (MMP-1); Ki = 0.5 nM for gelatinase A (MMP-2); Ki = 27 nM for stromelysin (MMP-3); Ki = 0.1 nM for neutrophil collagenase (MMP-8); and Ki = 0.2 nM for gelatinase B (MMP-9)]. Also prevents the release of TNF-α in vivo and in vitro and abrogates endotoxin-induced lethality in mice.
Biochem/physiol Actions
GM6001 promotes cardiovascular and hepatocellular function.
References
1) Saghatelian et al. (2004) Activity-based probes for the proteomic profiling of metalloproteases; Proc. Natl. Acad. Sci. USA, 101 10000
2) Galardy et al. (1994) Low molecular weight inhibitors in corneal ulceration; Ann. N.Y. Acad..Sci. 732 315
3) Yamamoto et al.(1998) Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors: An Examination of the Subsite Pocket; J. Med. Chem. 41 1209
4) Park et al. (2003) The intermediate S1- pocket of the endometase/matrilysin-2 active site revealed by enzyme inhibition kinetic studies, protein sequence analyses, and homology modeling; J. Biol. Chem. 278 51646
