Urokinase plasminogen activator as an anti-metastasis target: Inhibitor design principles, recent amiloride derivatives and issues with human/mouse species selectivity

Abstract

The urokinase plasminogen activator (uPA) is a widely studied anticancer drug target with multiple classes of inhibitors reported to date. Many of these inhibitors contain amidine or guanidine groups, while others lacking these show improved oral bioavailability. Most of the X-ray co-crystal structures of small molecule uPA inhibitors show a key salt bridge between the side-chain carboxylate of Asp189 in the S1 pocket of uPA. This review summarises the different classes of uPA inhibitors, their binding interactions and experimentally measured inhibitory potencies and highlights species selectivity issues with recent 6-substituted amiloride and 5‐N,N-(hexamethylene)amiloride (HMA) derivatives.

Disruption of Water Networks is the Cause of Human/Mouse Species Selectivity in Urokinase Plasminogen Activator (uPA) Inhibitors Derived from Hexamethylene Amiloride (HMA)

“…The urokinase plasminogen activation system (uPAS) comprises the trypsin-like serine protease (TLSP) urokinase plasminogen activator (uPA), its cognate cell-surface receptor (uPAR), and three endogenous serpin inhibitors: plasminogen activator inhibitors PAI-1, PAI-2, and PAI-3. − A major function of uPA is to catalyze the conversion of plasminogen to plasmin, which in turn activates multiple downstream proteases, including matrix metalloproteinases (MMPs) and cathepsins . Collectively, these activated proteases cause localized proteolysis that leads to basement membrane degradation and remodeling of the extracellular matrix. , As such, the uPAS is intimately involved in several physiological functions that require controlled tissue remodeling, including ovulation, , embryonic implantation, mammary gland involution, inflammatory reactions, wound healing, and clot lysis. , Dysregulated uPA activity causes tissue damage that has been linked to rheumatoid arthritis, , allergic vasculitis, xeroderma pigmentosum, multiple sclerosis, lymphangioleiomyomatosis, and chronic kidney disease .…”

Disruption of water networks is the cause of human/mouse species selectivity in urokinase plasminogen activator (uPA) inhibitors derived from hexamethylene amiloride (HMA)

“…The urokinase plasminogen activation system (uPAS) comprises the trypsin-like serine protease (TLSP) urokinase plasminogen activator (uPA), its cognate cell surface receptor (uPAR) and three endogenous serpin inhibitors; plasminogen activator inhibitors PAI-1, PAI-2 and PAI-3. [1][2][3][4][5][6] A major function of uPA is to catalyze the conversion of plasminogen to plasmin, which in turn activates multiple downstream proteases, including matrix metalloproteinases (MMPs) and cathepsins. 7 Collectively, these activated proteases cause localized proteolysis that leads to basement membrane degradation and remodelling of the extracellular matrix.…”