2. Academic Validation
  3. 4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress

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

  • Mol Cancer Ther. 2023 Dec 8. doi: 10.1158/1535-7163.MCT-23-0487.
Marissa L Calbert 1,  Gurushankar Chandramouly 1,  Clare M Adams 2,  Magali Saez-Ayala 3,  Tatiana Kent 4,  Mrityunjay Tyagi 1,  V S S Abhinav Ayyadevara 5,  Yifan Wang 6,  John J Krais 7,  John Gordon 8,  Jessica Atkins 9,  Monika M Toma 10,  Stéphane Betzi 3,  Andrew S Boghossian 11,  Matthew G Rees 11,  Melissa M Ronan 11,  Jennifer A Roth 11,  Aaron R Goldman 12,  Nicole Gorman 12,  Ramkrishna Mitra 1,  Wayne E Childers 13,  Xavier Graña 10,  Tomasz Skorski 5,  Neil Johnson 6,  Christian Hurtz 14,  Xavier Morelli 3,  Christine M Eischen 1,  Richard T Pomerantz 1
Affiliations

Affiliations

  • 1 Thomas Jefferson University, Philadelphia, PA, United States.
  • 2 Thomas Jefferson University, Philadelphia, Pennsylvania, United States.
  • 3 Centre de Recherche en Cancérologie de Marseille, Marseille, France.
  • 4 Thomas Jefferson University, United States.
  • 5 Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States.
  • 6 Fox Chase Cancer Center, Philadelphia, United States.
  • 7 Fox Chase Cancer Center, Philadelphia, PA, United States.
  • 8 Temple University School of Pharmacy, Philadelphia, United States.
  • 9 Temple University School of Medicine, Philadelphia, PA, United States.
  • 10 Temple University, Philadelphia, PA, United States.
  • 11 Broad Institute, Cambridge, MA, United States.
  • 12 The Wistar Institute, Philadelphia, PA, United States.
  • 13 Temple University School of Pharmacy, Philadelphia, PA, United States.
  • 14 Loma Linda University, Loma Linda, CA, United States.
PMID: 38064712 DOI: 10.1158/1535-7163.MCT-23-0487
Abstract

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.

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