AraC-FdUMP[10] Is a Next-Generation Fluoropyrimidine with Potent Antitumor Activity in PDAC and Synergy with PARG Inhibition

AraC-FdUMP[10] (CF10) is a second-generation polymeric fluoropyrimidine that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOI,FIRNOX, a standard-of-care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple cell lines including patient-derived lines) with IC(50)s in the nanomolar range and are nearly 1,000-fold more potent than 5-FU. The increased potency of CF10 relative to 5-FU correlated with enhanced TS inhibition and strong Top1 cleavage complex formation. Furthermore, CF10 displayed single-agent activity in PDAC murine xenografts without inducing weight loss. Through a focused drug synergy screen, we identified that combining CF10 with targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase, induces substantial DNA damage and apoptosis. This work moves CHO closer to a clinical trial for the treatment of PDAC. [GRAPHICS] .

Automated summary

CF10 is a novel drug for treating PDAC, more potent than 5-FU, effective in inhibiting PDAC cell survival by inhibiting TS and strong Top1 cleavage complex formation, and shows single-agent activity in murine models.