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Figure S5 from 4′-Ethynyl-2′-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress

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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

RNA-seq analysis of T-ALL Jurkat and DLBCL SUDHL-10 after 16-hour treatment with 1µM EdC.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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

French Infrastructure for Integrated Structural Biology (FRISBI)

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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.

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    Molecular Cancer Therapeutics

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