ly2334737

Description: LY2334737 is the orally bioavailable prodrug of gemcitabine that is cleaved systemically to gemcitabine, a nucleoside anticancer drug used in chemotherapy. As an orally available valproic acid ester of gemcitabine, which is a broad-spectrum antimetabolite with antineoplastic activity, LY2334737 has anticancer activity after activation following oral administration. Compared to gemcitabine, LY2334737 is able to avoid hydrolysis in enterocytes and the portal circulation thus avoiding first pass metabolism and increasing systemic gemcitabine availability. LY2334737 is hydrolyzed by carboxylesterase 2 (CES2) and releases gemcitabine systemically over a period of time consistent with formation rate-limited kinetics. In turn, gemcitabine is converted into the active metabolites difluorodeoxycytidine diphosphate and triphosphate (dFdCDP and dFdCTP) by deoxycytidine kinase. dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA replication; dFdCTP is incorporated into DNA, resulting in premature termination of DNA replication and eventually the induction of apoptosis.

References: Clin Cancer Res. 2013 Mar 1; 19(5):1159-68.