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Pharmaceuticals 2017, 10(3), 65; doi:10.3390/ph10030065

5-aza-2′,2′-Difluroro Deoxycytidine (NUC013): A Novel Nucleoside DNA Methyl Transferase Inhibitor and Ribonucleotide Reductase Inhibitor for the Treatment of Cancer

1
Epigenetics Pharma, 9270 SE 36th Pl, Mercer Island, WA 98040, USA
2
Department of Hematology, Affiliated Hospital of Weifang Medical University, Weifang 261000, China
3
Cleveland Clinic Taussig Cancer Institute and Case Comprehensive Cancer Center Cleveland, Cleveland, OH 44011, USA
*
Author to whom correspondence should be addressed.
Received: 25 November 2016 / Revised: 19 February 2017 / Accepted: 16 July 2017 / Published: 20 July 2017
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Abstract

Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit DNA methyl transferase. 5-aza-2′,2′-diflurorodeoxycytidine (NUC013) is a novel DNA methyl transferase and ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than decitabine in the NCI 60 cancer cell line panel. NUC013 is more active than decitabine against p53-null/mutant cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0.0025). The maximum tolerated dose in mice of NUC013 is greater than 120 mg/kg administered intravenously for three consecutive days a week for three weeks. With this regimen and a dose of 20 mg/kg in a human leukemia HL-60 (p53-null) NCr-nu/nu mouse xenograft model (n = 10/group), NUC013 demonstrated a survival benefit (saline median survival (MS) = 26.5 days, NUC013 MS = 32 days and hazard ratio (HR) = 0.26 (p = 0.032)). In a colon cancer LoVo (TP53 WT) xenograft, mice treated with decitabine at 5 mg/kg had worse survival than saline controls (decitabine MS = 31 days, saline MS > 60 days and HR = 26.89 (p < 0.0001)). At a dose of 20 mg/kg NUC013, mean tumor volume in the LoVo xenografts was lower than controls by 50.9% and at 40 mg/kg by 53.7% (both p < 0.0001). View Full-Text
Keywords: DNA methyl transferase; ribonucleotide reductase; nucleoside; NUC013; decitabine; 5-azacytidine; gemcitabine; p53 DNA methyl transferase; ribonucleotide reductase; nucleoside; NUC013; decitabine; 5-azacytidine; gemcitabine; p53
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MDPI and ACS Style

Daifuku, R.; Hu, Z.; Saunthararajah, Y. 5-aza-2′,2′-Difluroro Deoxycytidine (NUC013): A Novel Nucleoside DNA Methyl Transferase Inhibitor and Ribonucleotide Reductase Inhibitor for the Treatment of Cancer. Pharmaceuticals 2017, 10, 65.

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