8OOJ

Crystal structure of dCK C4S-S74E mutant in complex with EdC and UDP

Summary for 8OOJ

• Entry DOI: 10.2210/pdb8ooj/pdb
• Descriptor: Deoxycytidine kinase, URIDINE-5'-DIPHOSPHATE, 4-azanyl-1-[(2~{R},4~{S},5~{R})-5-ethynyl-5-(hydroxymethyl)-4-oxidanyl-oxolan-2-yl]pyrimidin-2-one, ... (4 entities in total)
• Functional Keywords: nucleoside kinase, phosphorylation, complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 133428.11

Authors

Saez-Ayala, M.,Rebuffet, E.,Betzi, S.,Morelli, X. (deposition date: 2023-04-05, release date: 2023-12-20, Last modification date: 2024-05-15)

Primary citation

Calbert, M.L.,Chandramouly, G.,Adams, C.M.,Saez-Ayala, M.,Kent, T.,Tyagi, M.,Ayyadevara, V.S.S.A.,Wang, Y.,Krais, J.J.,Gordon, J.,Atkins, J.,Toma, M.M.,Betzi, S.,Boghossian, A.S.,Rees, M.G.,Ronan, M.M.,Roth, J.A.,Goldman, A.R.,Gorman, N.,Mitra, R.,Childers, W.E.,Grana, X.,Skorski, T.,Johnson, N.,Hurtz, C.,Morelli, X.,Eischen, C.M.,Pomerantz, R.T.
4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.
Mol.Cancer Ther., 23:683-699, 2024

PubMed 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.

PubMed: 38064712
DOI: 10.1158/1535-7163.MCT-23-0487

Experimental method

X-RAY DIFFRACTION (2.1 Å)