Thymidylate synthase dimer disrupters induce DNA damage, halt cell growth, overcome drug resistance in colorectal cancer

Thymidylate synthase (TS) is an important target for cancer chemotherapy. Cells selected for high TS protein activity have low sensitivity to TS-targeting chemotherapeutic agents (5-FU and pemetrexed) and show cross- resistance to other chemotherapeutics (e.g., oxalilplatin). This causes failure of therapy in 30% of patients. To prevent/delay treatment-induced resistance, novel therapeutic strategies are required. In response to this need, we propose a new paradigm in TS inhibition consisting in small molecules, such as E7, that target the enzyme dimer interface and favor dissociation of the catalytically active dimer to the inactive monomers (Ddis). The Ddis are active in vivo against pancreatic cancer models.