Satellite Program The 47th Lorne Conference on Protein Structure and Function 2022

Disruption of water networks is the cause of human/mouse species selectivity in urokinase plasminogen activator (uPA) inhibitors derived from hexamethylene amiloride (HMA) (#33)

Nehad S. El Salamouni 1 2 3 , Benjamin J Buckley 1 2 3 4 , Longguang Jiang 5 , Mingdong Huang 5 , Marie Ranson 1 2 3 4 , Michael J Kelso 1 2 3 , Haibo Yu 1 2 3
  1. School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
  2. Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia
  3. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
  4. CONCERT-Translational Cancer Research Centre, Wollongong, NSW, Australia
  5. National Joint Biomedical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fuzhou, Fujian, China

The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target [1]. 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). A new analog 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.[2]

 

  1. El Salamouni et al. Urokinase plasminogen activator as an anti-metastasis target: Inhibitor design principles, recent amiloride derivatives and issues with human/mouse species selectivity, OSF Preprint https://osf.io/3z5m4/
  2. El Salamouni et al. Disruption of water networks is the cause of human/mouse species selectivity in urokinase plasminogen activator (uPA) inhibitors derived from hexamethylene amiloride (HMA), Chemrxiv. Preprint. https://doi.org/10.33774/chemrxiv-2021-c6lrq-v3