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NUC013 (5-aza-2′,2′-difluroro-deoxycytidine) is preclinically safer and more effective than decitabine (Pharmaceuticals 2017, 10, 65).  5-Azacytidines are hydrolyzed at the cytosine’s 6-position, but in vivo, the short half-life is governed by deamination.  For decitabine, attempts have been made to address these issues with continuous infusion, but use of such a regimen is limited by inconvenience and toxicity. A hydrophobic prodrug was developed for packaging in a hydrophobic matrix to protect NUC013 from hydrolysis and deamination.  In an aqueous environment, the hydrophobic moieties are readily hydrolyzed with release of NUC013 .  This was achieved by conjugating NUC013 with trimethylsilyl (TMS) at the 3’ and 5’ position (NUC041).  The half-life of NUC013 administered IV in mice is 20.1 minutes.  Below, PK following administration of a dose of 3mg of NUC041 IM in a PEG-phospholipid-depot to mice: Analyte   Cmax (ng/mL)    Tmax (hr)    t½ (hr)   AUCINF (hr·ng/mL)    MRTINF (hr) NUC041   4210   0.5  1.7  6261   2.6 NUC013   1333   1.0  3.4  5813   5.1 In an ongoing study, NUC041 was administered at a dose of 3mg qwk to nude mice with a NSCLC H-460 xenograft.  After 3 days of treatment (n=8), tumor starting volume had decreased by 4%.  However, toxicity, likely from vehicle, was also observed at this dose.     .

<strong>NUC041: a Prodrug of the DNA Methyl Transferase Inhibitor (DNMTI) and Ribonucleotide Reductase Inhibitor NUC013</strong>