Identification of novel molecules bind to the DNA polymerase gamma protein and investigation their effects on cancer cell

Successful cancer therapy depends on selective killing of tumor cells while sparing normal cells. This selectivity can be achieved through DNA repair-based synthetic lethal interactions. The synthetic lethal relationship between MLH1 and DNA polymerase γ (Pol γ) indicating that the inhibition of Pol γ may have a role for the selective treatment of nonpolyposis colorectal cancer arising from mismatch repair deficiency with MLH1 mutation without impairing normal cells. In this study, to identify the small molecules to which MLH1-deficient cancer cells are selectively cytotoxic, we screened MLH1-deficient (HCT116-VA) and MLH1-proficient (HCT116-V1) cancer cell lines with the Prestwick Chemical Library compounds that interact with Pol γ protein. Of 1200 molecules, seven lead molecules that directly bind to Pol γ were identified by surface plasmon resonance analysis. Among them one molecule, called Prestw-272, was found to be selectively lethal to HCT116 cells (IC50: 5,72 µM) lacking functional MLH1 compared to MLH1-proficient HCT116-V1 cells (IC50: 36x103 µM ) by real time cellular analysis. Pol γ-depleted HCT116-VA grown in the presence of 20 µM Prestw-272 were resistant to its antiproliferative effects, whereas control shRNA-HCT116-VA cells were highly sensitive to Prestw-272, suggesting that antiproliferative effect of Prestw-272 is Pol γ dependent. These data suggest that Prestw-272 may be used as a new potential molecule for the selective treatment of MLH1-deficient cancers.