TY - JOUR
T1 - 4'-Ethynyl-2'-Deoxycytidine(EdC)PreferentiallyTargets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress
AU - Calbert, Marissa L.
AU - Chandramouly, Gurushankar
AU - Adams, Clare M.
AU - Saez-Ayala, Magali
AU - Kent, Tatiana
AU - Tyagi, Mrityunjay
AU - Ayyadevara, V. S.S.Abhinav
AU - Wang, Yifan
AU - Krais, John J.
AU - Gordon, John
AU - Atkins, Jessica
AU - Toma, Monika M.
AU - Betzi, Stéphane
AU - Boghossian, Andrew S.
AU - Rees, Matthew G.
AU - Ronan, Melissa M.
AU - Roth, Jennifer A.
AU - Goldman, Aaron R.
AU - Gorman, Nicole
AU - Mitra, Ramkrishna
AU - Childers, Wayne E.
AU - Graña, Xavier
AU - Skorski, Tomasz
AU - Johnson, Neil
AU - Hurtz, Christian
AU - Morelli, Xavier
AU - Eischen, Christine M.
AU - Pomerantz, Richard T.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2024/5/1
Y1 - 2024/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85192112868
U2 - 10.1158/1535-7163.MCT-23-0487
DO - 10.1158/1535-7163.MCT-23-0487
M3 - Article
C2 - 38064712
AN - SCOPUS:85192112868
SN - 1535-7163
VL - 23
SP - 683
EP - 699
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -