Hypoxia-targeted bioreductive tyrosine kinase inhibitors with glutathione-depleting function.
Tyrosine kinase inhibitors may serve as ligands for kinases that are involved in normal cell differentiation or repair, thereby leading to toxicity. It may be possible to target such inhibitors to tumor cells by coupling them to hypoxia-activated bioreductive molecules. Such coupling can utilize or incorporate bonds that have a propensity to be preferentially oxidized by thiols such as intracellular glutathione (GSH). The resulting depletion of GSH may increase redox-mediated apoptosis. The resultant molecule is hence projected to act via multiple cell killing mechanisms: (i) inhibition of tumor kinases, (ii) tumor DNA disruption and (iii) causing increased redox-mediated apoptosis.
Sarangarajan
Rangaprasad
R
Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, USA.
Apte
Shireesh P
SP
Ugwu
Sydney O
SO
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D004247:DNA / Q000187:drug effects; D016503:Drug Delivery Systems; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D004247:DNA; D005978:Glutathione