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4801 Identification of a Novel Nucleoside Prodrug with Preferential Activity in Lymphoma and Leukemia Subtypes

Program: Oral and Poster Abstracts
Session: 802. Chemical Biology and Experimental Therapeutics: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Lymphoid Leukemias, ALL, Lymphomas, non-Hodgkin lymphoma, drug development, Diseases, Therapies, Lymphoid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Marissa L Calbert, BSc1,2, Gurushankar Chandramouly, PhD1*, Tatiana Kent, PhD1*, Clare M Adams, PhD3*, Mrityunjay Tyagi, PhD1*, Yifan Wang, PhD4*, John Krais, PhD4*, Hoora Shaghaghi, PhD5*, Jessica Atkins, BSc2*, Tomasz Skorski, MD, PhD2, Neil Johnson, PhD4*, Christine M Eischen, PhD3 and Richard Pomerantz, PhD1*

1Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA
2Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
3Sidney Kimmel Cancer Center, Department of Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA
4Fox Chase Cancer Center, Philadelphia, PA
5Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA

Nucleoside analogs are a highly successful prodrug class that have been approved to treat various viral, bacterial and fungal infections, as well as cancers. We identify a 4’-modified deoxycytidine analog (EdC) as an anti-cancer nucleoside prodrug that exhibits nanomolar IC50 in lymphoma and leukemia subtypes, such as B- and T-cell acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL) and DNMT3A-mutant acute myeloid leukemia (AML) cell lines. Remarkably, EdC shows little to no activity in cancer cells derived from solid tumors and non-tumorigenic cells. Unlike cytotoxic nucleotide chain terminator anti-cancer drugs such as cytarabine (AraC) and gemcitabine, EdC acts as a monophosphate and arrests replication via suppression of dNTP metabolism. This mechanism of action (MOA) results in a significantly delayed DNA damage response (DDR). Notably, EdC completely evades cytidine deaminase, a major cytidine prodrug resistance mechanism. Finally, in vivo studies demonstrate EdC’s ability to rapidly regress DLBCL tumors as a single agent in mice without any apparent toxicity. Future studies aim to further elucidate the MOA of EdC and identify genetic biomarkers to further develop EdC as a clinical candidate for DLBCL, ALL and DNMT3A-mutant AML.

Disclosures: Eischen: Abbvie: Research Funding. Pomerantz: Recombination Therapeutics LLC: Current Employment, Research Funding.

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