Decitabine, an FDA-approved DNA methyltransferase 1 (DMNT1) inhibitor, is a viable treatment option for patients with myelodysplastic syndrome (MDS). Decitabine, however, exhibits poor oral bioavailability due to its rapid metabolism catalyzed by cytidine deaminase (CDA) in the liver and kidneys. This prompted us to develop small molecule CDA inhibitors that can be co-administered with decitabine with the ultimate objective of developing an oral form of this hypomethylating agent. Here we describe the discovery of cedazuridine, an orally available CDA inhibitor capable of blocking CDA-mediated metabolism of decitabine. Cedazuridine exhibited enhanced stability at low pH compared to tetrahydrouridine, a prototype CDA inhibitor, and boosted plasma levels of decitabine in Rhesus monkeys following oral co-administration. A PK/PD-guided phase I dose-finding study revealed that a fixed oral combination of 30-40 mg of decitabine and 100 mg of cedazuridine closely emulates the current dosing regimen of decitabine (1-hour IV infusion of 20 mg/m<sup>2</sup>), demonstrating the potential of ASTX727 as an effective oral treatment option for patients with MDS.

Discovery of ASTX727, an oral combination of decitabine and cedazuridine for the treatment of myelodysplastic syndrome (MDS)

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.