Development of Enzyme Deregulators as Antiproliferative Agents Using Yeast Genetics and Structural Biology
Ribonucleotide reductase is a critical enzyme for the synthesis of DNA bases. It is crucial for cell growth, repair of DNA damage and maintenance of genetic integrity. RNR is a popular target for anticancer drug design. One of the most promising anticancer agents to enter the clinic in the last few years, gemicitabine, as well as one of the oldest, hydroxyurea, target RNR. Both agents, however, target the enzymes's catalytic site resulting in a general cytotoxic effect.
We propose to use a combination of genetic and structural methods to determine whether deregulation of RNR, as opposed to its direct inhibition, can be a therapeutically useful strategy for the treatment of specific human cancers. Specifically, we plan to determine whether such a strategy allows the inhibition of growth of cells deficient in one or more components of mismatch repair. The Simon Lab has recently isolated a point mutant of yeast RNR which is lethal in strains deficient in mismatch repair functions. The point mutation is located in the enzyme allosteric regulatory site. The Stoddard Lab has recently demonstrated the feasibility of using structure-based methods to design novel allosteric effectors and deregulators of enzyme activity. The collaboration of these groups and the interdisciplinary training of a postdoctoral fellow in both labs during this project is an attractive approach to this research project.