DEVELOPMENT OF 4'-ETHYNYL-2'-DEOXYCYTIDINE (EdC), A REPLICATION-STRESS INDUCING NUCLEOSIDE ANALOG PRODRUG WITH PREFERENTIAL ACTIVITY IN LEUKEMIA AND LYMPHOMA SUBTYPES

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 induces 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.

Grantor dc:publisher

Temple University. Libraries

Year dc:date.issued

2024

Author dc:creator

• Calbert, Marissa

Advisor dc:contributor.advisor

• Skorski, Tomasz

Committee members dc:contributor.committeemember

• Graña-Amat, Xavier
• Pomerantz, Richard
• Tempera, Italo
• Johnson, Neil
• Scott, Charles P.

• Cellular biology
• Pharmaceutical sciences
• Genetics
• Cancer therapeutics
• DNA damage response
• DNA replication
• Leukemia
• Lymphoma
• Nucleoside analog

Statement dc:rights

• IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/20.500.12613/10189

OAI identifier oai:identifier

oai:scholarshare.temple.edu:20.500.12613/10189