Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Molecular cancer therapeutics, 2024-05, Vol.23 (5), p.683

Ort / Verlag

United States

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.