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Our laboratory has a long-standing interest in the development of new drugs for the treatment of cancer. Current efforts are focused on the design, synthesis and activation mechanisms of novel prodrugs that undergo enzyme-catalyzed activation in the tumor cell to liberate a toxic phosphoramidate, phosphate or phosphonate. Several different targets are under investigation to exploit this approach. First, we have applied this novel prodrug chemistry to the design and synthesis of novel phosphotyrosine peptidomimetic prodrugs (1) that interfere with cell signaling pathways regulating cell proliferation. Cell-based assays have confirmed that the phosphotyrosine peptidomimetic prodrugs deliver the bioactive phosphate and inhibit tumor cell proliferation. We have also extended this chemistry to the synthesis of phosphatase-resistant phosphopeptidomimetics by incorporating a difluoromethylphosphonate group as a phosphate surrogate. This provides technology for the design, synthesis and intracellular delivery of long-lived phosphate-based antagonists and phosphatase inhibitors. In collaboration with the Geahlen lab, we have identified a novel cancer target and are designing novel inhibitors directed at that target. Second, in collaboration with the Gibbs lab we have developed a novel series of prodrugs (2) designed to inhibit farnesyl transferase, an important enzymatic target in tumor cells. Although these prodrugs have minimal activity as single agents, in combination with one of the widely used statin drugs they are nanomolar inhibitors of tumor cell proliferation. Finally, we are using the phosphoramidate prodrug technology to develop a novel class of drug-dendrimer nanoparticles that will facilitate targeted delivery of cancer drugs.
Our laboratory has a long-standing interest in the development of new drugs for the treatment of cancer. Current efforts are focused on the design, synthesis and activation mechanisms of novel prodrugs that undergo enzyme-catalyzed activation in the tumor cell to liberate a toxic phosphoramidate, phosphate or phosphonate. Several different targets are under investigation to exploit this approach. First, we have applied this novel prodrug chemistry to the design and synthesis of novel phosphotyrosine peptidomimetic prodrugs (1) that interfere with cell signaling pathways regulating cell proliferation. Cell-based assays have confirmed that the phosphotyrosine peptidomimetic prodrugs deliver the bioactive phosphate and inhibit tumor cell proliferation. We have also extended this chemistry to the synthesis of phosphatase-resistant phosphopeptidomimetics by incorporating a difluoromethylphosphonate group as a phosphate surrogate. This provides technology for the design, synthesis and intracellular delivery of long-lived phosphate-based antagonists and phosphatase inhibitors. In collaboration with the Geahlen lab, we have identified a novel cancer target and are designing novel inhibitors directed at that target. Second, in collaboration with the Gibbs lab we have developed a novel series of prodrugs (2) designed to inhibit farnesyl transferase, an important enzymatic target in tumor cells. Although these prodrugs have minimal activity as single agents, in combination with one of the widely used statin drugs they are nanomolar inhibitors of tumor cell proliferation. Finally, we are using the phosphoramidate prodrug technology to develop a novel class of drug-dendrimer nanoparticles that will facilitate targeted delivery of cancer drugs.
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John J. Reiners Jr,Patricia A. Mathieu, Mary Gargano, Irene George,Yimin Shen, John F. Callaghan,Richard F. Borch,Raymond R. Mattingly
CANCERSno. 1 (2024): 89
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