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Journal of Pharmacology and Experimental Therapeutics

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5-Aza-4'-thio-2'-deoxycytidine, a new orally bioavailable non-toxic "best-in-class" DNMT1 depleting agent in clinical development

William B Parker and Jaideep V Thottassery
Journal of Pharmacology and Experimental Therapeutics September 9, 2021, JPET-MR-2021-000758; DOI: https://doi.org/10.1124/jpet.121.000758
William B Parker
1PNP Therapeutics, United States
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  • For correspondence: jthottassery1@icloud.com
Jaideep V Thottassery
2Oncology, UDG Healthcare - Ashfield Advisory, United States
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  • For correspondence: jthottassery1@icloud.com
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Abstract

DNA methyltransferase 1 (DNMT1) is an enzyme that functions as a maintenance methyltransferase during DNA replication, and depletion of this enzyme from cells is considered to be a rational goal in DNA methylation dependent disorders. Two DNMT1 depleting agents aza-dCyd (5-aza-2'-deoxycytidine, decitabine) and aza-Cyd (5-aza-cytidine, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia, and have also been investigated for non-oncology indications such as sickle cell disease. However, these agents have several off-target activities leading to significant toxicities that limit dosing and duration of treatment. Development of more selective inhibitors of DNMT1 could therefore afford treatment for long durations at effective doses. We have discovered that 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) is as effective as aza-dCyd in depleting DNMT1 in mouse tumor models, but with markedly low toxicity. In this review we describe the preclinical studies that led to the development of aza-T-dCyd as a superior DNMT1 depleting agent with respect to aza-dCyd, and will describe its pharmacology, metabolism, and mechanism of action. In an effort to understand why aza-T-dCyd is a more selective DNMT1 depleting agent than aza-dCyd, we will also compare and contrast the activities of these two agents.

Significance Statement Aza-T-dCyd is a potent DNMT1 depleting agent. Although similar in structure to decitabine (aza-dCyd) its metabolism and mechanism of action is different than that of aza-dCyd, resulting in less off target activity and less toxicity. The larger therapeutic index of aza-T-dCyd (DNMT1 depletion vs toxicity) in mice suggests that it would be a better clinical candidate to selectively deplete DNMT1 from target cells and determine whether or not depletion of DNMT1 is an effective target for various diseases.

  • DNA methylation
  • Nucleoside/Nucleotide derivatives
  • nucleosides
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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5-Aza-4'-thio-2'-deoxycytidine, a new DNMT1 depleting agent

William B Parker and Jaideep V Thottassery
Journal of Pharmacology and Experimental Therapeutics September 9, 2021, JPET-MR-2021-000758; DOI: https://doi.org/10.1124/jpet.121.000758

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OtherMinireview

5-Aza-4'-thio-2'-deoxycytidine, a new DNMT1 depleting agent

William B Parker and Jaideep V Thottassery
Journal of Pharmacology and Experimental Therapeutics September 9, 2021, JPET-MR-2021-000758; DOI: https://doi.org/10.1124/jpet.121.000758
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