title: Tumor-targeting of EGFR inhibitors by hypoxia-mediated activation.
abstract: The development of receptor tyrosine-kinase inhibitors (TKIs) was a major step forward in cancer treatment. However, the therapy with TKIs is limited by strong side effects and drug resistance. The aim of this study was the design of novel epidermal growth factor receptor (EGFR) inhibitors that are specifically activated in malignant tissue. Thus, a Co(III) -based prodrug strategy for the targeted release of an EGFR inhibitor triggered by hypoxia in the solid tumor was used. New inhibitors with chelating moieties were prepared and tested for their EGFR-inhibitory potential. The most promising candidate was coupled to Co(III) and the biological activity tested in cell culture. Indeed, hypoxic activation and subsequent EGFR inhibition was proven. Finally, the compound was tested in vivo, also revealing potent anticancer activity.
authors: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria).
authors: Claudia
authors: C
authors: Karnthaler-Benbakka
authors: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna (Austria).
authors: Diana
authors: D
authors: Groza
authors: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna (Austria).
authors: Kushtrim
authors: K
authors: Kryeziu
authors: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria).
authors: Verena
authors: V
authors: Pichler
authors: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria).
authors: Alexander
authors: A
authors: Roller
authors: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna (Austria); Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna (Austria).
authors: Walter
authors: W
authors: Berger
authors: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna (Austria); Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna (Austria).
authors: Petra
authors: P
authors: Heffeter
authors: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria); Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna (Austria).
authors: Christian R
authors: CR
authors: Kowol
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D003035:Cobalt; D066246:ErbB Receptors
keywords: anticancer drugs; cobalt; hypoxia; prodrugs; tyrosine-kinase inhibitors