Disruption of Water
Networks is the Cause of Human/Mouse
Species Selectivity in Urokinase Plasminogen Activator (uPA) Inhibitors
Derived from Hexamethylene Amiloride (HMA)
posted on 2021-12-13, 19:34authored byNehad S El Salamouni, Benjamin J. Buckley, Longguang Jiang, Mingdong Huang, Marie Ranson, Michael J. Kelso, Haibo Yu
The
urokinase plasminogen activator (uPA) plays a critical role
in tumor cell invasion and migration and is a promising antimetastasis
target. 6-Substituted analogues of 5-N,N-(hexamethylene)amiloride
(HMA) are potent and selective uPA inhibitors that lack the diuretic
and antikaliuretic properties of the parent drug amiloride. However,
the compounds display pronounced selectivity for human over mouse
uPA, thus confounding interpretation of data from human xenograft
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). Analogue 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 antimetastasis drugs.