Definition

A phosphoramidate derivative of the monophosphate form of cordycepin (3′-deoxyadenosine; 3′-dA), an adenosine derivative first isolated from Cordyceps sinensis, with potential antineoplastic, antioxidant, and anti-inflammatory activities. Upon administration and cellular uptake of NUC-7738 by passive diffusion, cordycepin monophosphate (3′-dAMP) is converted into its active anti-cancer metabolite 3′-deoxyadenosine triphosphate (3′-dATP). 3′-dATP functions as a ribonucleoside analogue and competes with ATP during transcription. Therefore, this agent causes RNA synthesis inhibition, inhibits cellular proliferation, and induces apoptosis. Also, 3′-dAMP activates AMP-activated protein kinase (AMPK) and reduces mammalian target of rapamycin (mTOR) signaling. This prevents the hyperphosphorylation of the translation repressor protein 4E-BP1. This results in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family, plays an important role in the PI3K/AKT/mTOR signaling pathway that regulates cell growth and proliferation, and its expression or activity is frequently dysregulated in human cancers. Compared to cordycepin alone, the addition of the phosphoramidate moiety may overcome cancer resistance and allow for greater cytotoxicity as NUC-7738 does not require a nucleoside transporter for cellular uptake, is independent of enzymatic activation by adenosine kinase (AK) and is not susceptible to enzymatic degradation by adenosine deaminase (ADA). Altogether, this may help overcome cancer resistance to cordycepin.