4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress

Marissa L Calbert, Gurushankar Chandramouly, Clare M Adams, Magali Saez-Ayala, Tatiana Kent, Mrityunjay Tyagi, V S S Abhinav Ayyadevara, Yifan Wang, John J. Krais, John Gordon, Jessica Atkins, Monika M Toma, Stéphane Betzi, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Aaron R Goldman, Nicole Gorman, Ramkrishna MitraWayne E Childers, Xavier Graña, Tomasz Skorski, Neil Johnson, Christian Hurtz, Xavier Morelli, Christine M Eischen, Richard T Pomerantz

Research output: Contribution to journalArticlepeer-review


Anticancer nucleosides are effective against solid tumors and hematological malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induced replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å co-crystal structure of DCK bound to EdC and UDP reveals how the rigid 4'-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared to FDA approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a pre-clinical nucleoside prodrug candidate for DLBCL and ALL.

Original languageEnglish
Pages (from-to)683-699
Number of pages17
JournalMolecular Cancer Therapeutics
Issue number5
Early online dateNov 8 2023
StatePublished - May 1 2024


  • Animals
  • Cell Line, Tumor
  • Deoxycytidine Kinase/metabolism
  • Deoxycytidine/analogs & derivatives
  • Humans
  • Leukemia/drug therapy
  • Lymphoma/drug therapy
  • Mice
  • Xenograft Model Antitumor Assays


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