Activating the MSH2/MSH6 Apoptotic Pathway in Cancer Cells Using Non-Reserpine Compounds

DNA mismatch repair (MMR) is a system that is highly conserved in both prokaryotes and eukaryotes. The heterodimeric protein MutSα and a suite of associated proteins are essential in the recognition and repair of DNA afflicted with mispaired bases and short insertion/deletion loops, but are also implicated in funneling damaged cells towards apoptosis via a key conformational change in a subunit of the MutSα complex. This conformation can be bound specifically by the small molecule reserpine. Molecular dynamics modeling and virtual screening were used to identify additional small molecule novel ligands with the predicted ability to selectively bind this “death” conformation of MutSα. These novel ligands were demonstrated to possess cytotoxicity similar to that of reserpine. As MMR deficiency has been demonstrated to confer a degree of resistance to some chemotherapeutic agents, exploiting this novel apoptotic pathway may prove to be a valid niche treatment in particular classes of cancers in which MMR proteins have been mutated