36 The leadcompound of this series 1 was transported into tumorcells by RFC and PCFT (FR uptake was not evaluated).5 Compound 1 accumulated in the cytosol andmitochondria whereupon it inhibited C1 metabolism at critical mitochondrial(SHMT2) and cytosolic (SHMT1, GARFTase, AICARFTase) targets.5,36 Analogue 1 showed in vitro antitumorefficacy toward pancreatic cancer, lung adenocarcinoma, and coloncancer cell lines, with promising in vivo efficacyagainst early and late-stage MIA PaCa 2 pancreatic cancer xenografts.5,36. Here, SHMT2 is linked to familial pancreatic carcinoma.