Identification of a Novel Nucleoside Prodrug with Preferential Activity in Lymphoma and Leukemia Subtypes

Nucleoside analogs are a highly successful prodrug class that have been approved to treat various viral, bacterial and fungal infections, as well as cancers. We identify a 4'-modified deoxycytidine analog (EdC) as an anti-cancer nucleoside prodrug that exhibits nanomolar IC50 in lymphoma and leukemia subtypes, such as B- and T-cell acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL) and DNMT3A-mutant acute myeloid leukemia (AML) cell lines. Remarkably, EdC shows little to no activity in cancer cells derived from solid tumors and non-tumorigenic cells. Unlike cytotoxic nucleotide chain terminator anti-cancer drugs such as cytarabine (AraC) and gemcitabine, EdC acts as a monophosphate and arrests replication via suppression of dNTP metabolism. This mechanism of action (MOA) results in a significantly delayed DNA damage response (DDR). Notably, EdC completely evades cytidine deaminase, a major cytidine prodrug resistance mechanism. Finally, in vivo studies demonstrate EdC's ability to rapidly regress DLBCL tumors as a single agent in mice without any apparent toxicity. Future studies aim to further elucidate the MOA of EdC and identify genetic biomarkers to further develop EdC as a clinical candidate for DLBCL, ALL and DNMT3A-mutant AML.