Article ; Online: 5-Aza-4'-thio-2'-deoxycytidine, a New Orally Bioavailable Nontoxic "Best-in-Class": DNA Methyltransferase 1-Depleting Agent in Clinical Development.
The Journal of pharmacology and experimental therapeutics
2021 Volume 379, Issue 3, Page(s) 211–222
Abstract: DNA methyltransferase (DNMT) 1 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 ... ...
| Abstract | DNA methyltransferase (DNMT) 1 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 5-aza-2'-deoxycytidine (aza-dCyd, decitabine) and 5-aza-cytidine (aza-Cyd, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia and have also been investigated for nononcology 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 of 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. |
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| MeSH term(s) | Administration, Oral ; Animals ; Biological Availability ; DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors ; DNA (Cytosine-5-)-Methyltransferase 1/metabolism ; Deoxycytidine/chemical synthesis ; Deoxycytidine/pharmacology ; Drug Development/methods ; Drug Development/trends ; Humans |
| Chemical Substances | Deoxycytidine (0W860991D6) ; DNA (Cytosine-5-)-Methyltransferase 1 (EC 2.1.1.37) ; DNMT1 protein, human (EC 2.1.1.37) |
| Language | English |
| Publishing date | 2021-09-09 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review |
| ZDB-ID | 3106-9 |
| ISSN | 1521-0103 ; 0022-3565 |
| ISSN (online) | 1521-0103 |
| ISSN | 0022-3565 |
| DOI | 10.1124/jpet.121.000758 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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