TY - JOUR
T1 - 4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets 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 hematological 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 induced replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å co-crystal 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 to FDA approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a pre-clinical nucleoside prodrug candidate for DLBCL and ALL.
AB - Anticancer nucleosides are effective against solid tumors and hematological 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 induced replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å co-crystal 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 to FDA approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a pre-clinical nucleoside prodrug candidate for DLBCL and ALL.
KW - Animals
KW - Cell Line, Tumor
KW - Deoxycytidine Kinase/metabolism
KW - Deoxycytidine/analogs & derivatives
KW - Humans
KW - Leukemia/drug therapy
KW - Lymphoma/drug therapy
KW - Mice
KW - Xenograft Model Antitumor Assays
UR - https://pubmed.ncbi.nlm.nih.gov/38064712/
UR - http://www.scopus.com/inward/record.url?scp=85192112868&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-23-0487
DO - 10.1158/1535-7163.MCT-23-0487
M3 - Article
C2 - 38064712
SN - 1535-7163
VL - 23
SP - 683
EP - 699
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -