Molecular cancer therapeutics · 2024
4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Calbert Marissa L, Chandramouly Gurushankar, Adams Clare M, Saez-Ayala Magali, Kent Tatiana, Tyagi Mrityunjay, Ayyadevara V S S Abhinav, Wang Yifan, Krais John J, Gordon John, Atkins Jessica, Toma Monika M, Betzi Stéphane, Boghossian Andrew S, Rees Matthew G, Ronan Melissa M, Roth Jennifer A, Goldman Aaron R, Gorman Nicole, Mitra Ramkrishna, Childers Wayne E, Graña Xavier, Skorski Tomasz, Johnson Neil, Hurtz Christian, Morelli Xavier, Eischen Christine M, Pomerantz Richard T
Аннотация
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.