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Targeting biosynthetic pathways for inducing uracil stress. Uracil in DNA is often the result of a dUTP/dTTP imbalance, caused by targeting thymidine production. 5-FU was the first anti-cancer strategy targeting TYMS, dating back to 1957, and remains a first-line strategy for gastrointestinal, head and neck, and breast cancers. Pemetrexed is an anti-folate agent that targets TYMS, DHFR, and GARFT. It was FDA-approved in 2007 and is primarily used in NSCLC. TAS-102 comprises TFT and tipiracil, and when converted to TFT-MP, it inhibits TYMS. It was approved in 2017. TH9619 targets the DC domain of MTHFD1, which creates a folate trap in MTHFD2-expressing cancer cells32and represents a novel way to target thymidine production. TAS-114 is a dUTPase inhibitor, and while not having anti-cancer efficacy as monotherapy, it synergizes with 5-FU or TH9619.

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