| Institution: | 1. School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia;2. Illawarra Health and Medical Research Institute, NSW 2522, Australia;3. Molecular Horizons, University of Wollongong, NSW 2522, Australia;4. National Joint Biomdical Engineering Research Centre on Photodynamic Technologies, Fuzhou University, Fuzhou 350116, China;5. Graduate School of Medicine, University of Wollongong, NSW 2522, Australia;6. Department of Microbiology and Immunology, University of Otago, Otago 9016, New Zealand;7. Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, NY 10065, USA;8. Chemical Biology Program, Memorial Sloan Kettering Cancer Centre, NY 10065, USA |
| 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. |
