6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease

  • Bioorg Med Chem Lett. 2019 Dec 15;29(24):126753. doi: 10.1016/j.bmcl.2019.126753.
Benjamin J Buckley  1 ,  Hiwa Majed  1 ,  Ashraf Aboelela  1 ,  Elahe Minaei  2 ,  Longguang Jiang  3 ,  Karen Fildes  4 ,  Chen-Yi Cheung  5 ,  Darren Johnson  6 ,  Daniel Bachovchin  7 ,  Gregory M Cook  5 ,  Mingdong Huang  3 ,  Marie Ranson  8 ,  Michael J Kelso  9
Affiliations
  • 1. School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia.
  • 2. Illawarra Health and Medical Research Institute, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia.
  • 3. National Joint Biomdical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fuzhou 350116, China.
  • 4. Illawarra Health and Medical Research Institute, NSW 2522, Australia; Graduate School of Medicine, University of Wollongong, NSW 2522, Australia.
  • 5. Department of Microbiology and Immunology, University of Otago, Otago 9016, New Zealand.
  • 6. Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, NY 10065, USA.
  • 7. Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, NY 10065, USA; Chemical Biology Program, Memorial Sloan Kettering Cancer Centre, NY 10065, USA.
  • 8. School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia. Electronic address: [email protected].
  • 9. School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia. Electronic address: [email protected].
PMID: 31679971 DOI: 10.1016/j.bmcl.2019.126753
Abstract

The oral K+-sparing diuretic amiloride shows anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, Ki = 2.4 µM), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies. In applying the selective optimization of side-activity (SOSA) approach, a focused library of twenty two 6-substituted amiloride derivatives were prepared, with multiple examples displaying uPA inhibitory potencies in the nM range. X-ray co-crystal structures revealed that the potency increases relative to amiloride arise from increased occupancy of uPA's S1β subsite by the appended 6-substituents. Leading compounds were shown to have high selectivity over related trypsin-like serine proteases and no diuretic or anti-kaliuretic effects in rats. Compound 15 showed anti-metastatic effects in a xenografted mouse model of late-stage lung metastasis.

Keywords
Amiloride; Anti-metastatic; Cancer; Metastasis; Selective optimisation of side-activity; Trypsin-like serine protease; Urokinase plasminogen activator; uPA.