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 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.

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)