Bjoern Bielec1, Hemma Schueffl2, Alessio Terenzi3, Walter Berger4, Petra Heffeter5, Bernhard K Keppler6, Christian R Kowol7. 1. Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria. 2. Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria. 3. Donostia International Physics Center, Paseo Manuel de Lardizabal 4, Donostia 20018, Spain. 4. Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; Research Cluster ''Translational Cancer Therapy Research'', Vienna, Austria. 5. Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; Research Cluster ''Translational Cancer Therapy Research'', Vienna, Austria. Electronic address: petra.heffeter@meduniwien.ac.at. 6. Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Cluster ''Translational Cancer Therapy Research'', Vienna, Austria. 7. Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Cluster ''Translational Cancer Therapy Research'', Vienna, Austria. Electronic address: christian.kowol@univie.ac.at.
Abstract
Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or -overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib.
Despite the huge success of n class="Gene">tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized withthe nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of bothprodrugs was investigated against ALK- and c-MET-dependent or -overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib.
Authors: Marlene Mathuber; Hemma Schueffl; Orsolya Dömötör; Claudia Karnthaler; Éva A Enyedy; Petra Heffeter; Bernhard K Keppler; Christian R Kowol Journal: Inorg Chem Date: 2020-11-21 Impact factor: 5.165
Authors: Marlene Mathuber; Michael Gutmann; Mery La Franca; Petra Vician; Anna Laemmerer; Patrick Moser; Bernhard K Keppler; Walter Berger; Christian R Kowol Journal: Inorg Chem Front Date: 2021-03-30 Impact factor: 6.569