NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells

Muhammed Akbar Shahid*, In Hwa Um, Mustafa Elshani, Ying Zhang, David James Harrison

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Acute myeloid leukemia (AML) stem cells are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of AML leukaemia stem cells (LSCs) and therefore, targeting β-catenin is a potential therapeutic strategy. NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA) monophosphate, is specifically designed to generate the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP) intracellularly, bypassing key limitations of breakdown, transport, and activation. NUC-7738 is currently in a Phase I/II clinical study for the treatment of patients with advanced solid tumors. Protein expression and immunophenotypic profiling revealed that NUC-7738 caused apoptosis in AML cell lines through reducing PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) resulting in reduced β-catenin, c-Myc and CD44 expression. NUC-7738 reduced β-catenin nuclear expression in AML cells. NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells.
Original languageEnglish
Article numbere0278209
Number of pages13
JournalPLoS ONE
Issue number12
Publication statusPublished - 15 Dec 2022


Dive into the research topics of 'NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells'. Together they form a unique fingerprint.

Cite this