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

2021 ◽  
Author(s):  
Nehad S El Salamouni ◽  
Benjamin J Buckley ◽  
Marie Ranson ◽  
Michael J Kelso ◽  
Haibo Yu
Keyword(s):  
Plasminogen Activator ◽  
Oral Bioavailability ◽  
Drug Target ◽  
Salt Bridge ◽  
Urokinase Plasminogen Activator ◽  
Side Chain ◽  
X Ray ◽  
Species Selectivity ◽  
Mouse Species ◽  
Amiloride Derivatives

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.

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

2021 ◽  
Author(s):  
Nehad El Salamouni ◽  
Benjamin Buckley ◽  
Longguang Jiang ◽  
Mingdong Huang ◽  
Marie Ranson ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Critical Role ◽  
Parent Drug ◽  
Urokinase Plasminogen Activator ◽  
Water Networks ◽  
Invasion And Migration ◽  
Species Selectivity ◽  
And Migration ◽  
Experimental Findings ◽  
Hexamethylene Amiloride

The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.

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