2. Academic Validation
  3. 6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease

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

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: mranson@uow.edu.au.
  • 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: mkelso@uow.edu.au.
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.

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