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. © 2006 Lippincott Williams & Wilkins.