American Association for Cancer Research
Browse
mct-23-0487_table_s4_suppst4.xlsx (9.4 kB)

Table S4 from 4′-Ethynyl-2′-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress

Download (9.4 kB)
dataset
posted on 2024-05-02, 07:45 authored by 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 Mitra, Wayne E. Childers, Xavier Graña, Tomasz Skorski, Neil Johnson, Christian Hurtz, Xavier Morelli, Christine M. Eischen, Richard T. Pomerantz

Individual blood concentrations (ng/mL) and pharmacokinetic parameters for EdC after IP injection.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

Alex's Lemonade Stand Foundation for Childhood Cancer (ALSF)

French Infrastructure for Integrated Structural Biology (FRISBI)

History

ARTICLE ABSTRACT

Anticancer nucleosides are effective against solid tumors and hematologic 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 induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å cocrystal 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 with FDA-approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a preclinical nucleoside prodrug candidate for DLBCL and ALL.

Usage metrics

    Molecular Cancer Therapeutics

    Categories

    Keywords

    Dna Damage And RepairDNA damageHematological CancersLeukemiasLymphomas

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC