Human
urokinase-type plasminogen activator (uPA or uPA) has been implicated in the regulation and control of basement membrane and interstitial protein degradation. Since
Urokinase plays a role in tissue remodeling, it may be responsible, in part, for the
disease progression of
cancer. Inhibitors of
urokinase may then be useful in the treatment of
cancer by retarding
tumor growth and
metastasis.
Urokinase is a multidomain
protein, two regions of the
protein are most responsible for the observed proteolytic activity in
cancer disease and progression. The N-terminal domain or ATF binds to a
Urokinase receptor (uPAR) on the cell surface and the C-terminal
serine protease domain, then, activates
plasminogen to
plasmin, beginning a cascade of events leading to the progression of
cancer. Investigations of
urokinase inhibition has been an area of ongoing research for the past 3 decades. It began with the discovery of small natural and unnatural
amino acid derivatives or
peptide analogs which exhibited weak inhibition of uPA. The last decade has seen the generation of several classes of potent and selective
Urokinase inhibitor directed to the
serine protease domain of the
protein which have shown potential anti-
cancer effects. The availability of structural information of
enzyme-inhibitor complexes either by nuclear magnetic spectroscopy (NMR) or crystallography has allowed a detailed analysis of inhibitor
protein interactions that contribute to observed inhibitor potency. Structural studies of specific inhibitor-uPA complexes will be discussed as well as the contributions of specific inhibitor
protein interactions that are important for overall inhibitor potency. These data were used to discover a class of
urokinase inhibitor based on the
2-Naphthamidine template that exhibits potent
urokinase inhibition and excellent selectivity for
urokinase over similar
trypsin family
serine proteases.