Targeting DNA mismatches with rhodium metalloinsertors
DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch repair (MMR)-deficient cancers. These rhodium metalloinsertors bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique among small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers.
© 2016 Published by Elsevier B.V. Received 30 November 2015; Received in revised form 7 January 2016; Accepted 11 January 2016. We are grateful to our coworkers and collaborators in elucidating this chemistry and to the NIH for their support of this research (GM33309). We also thank the United States Department of Defense for an NDSEG research fellowship to K.M.B.
Accepted Version - nihms754571.pdf