About the event
Speaker: Prof. Takashi Tsukamoto, Medicinal Chemistry, Johns Hopkins Drug Discovery Program, Associate Professor of Neurology, Johns Hopkins University
Title: Discovery of ASTX727 (INQOVI®), an oral combination of decitabine and cedazuridine for the treatment of myelodysplastic syndromes
Abstract: Cedazuridine is an orally available cytidine deaminase (CDA) inhibitor capable of blocking CDA-mediated metabolism of decitabine, an FDA-approved DNA methyltransferase 1 inhibitor. 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 clinical studies revealed that a fixed oral combination of 35 mg of decitabine and 100 mg of cedazuridine closely emulates the current dosing regimen of decitabine (1-hour IV infusion of 20 mg/m2), leading to FDA approval of the oral combination as Inqovi in 2020. This lecture covers the rationale behind the molecular design, synthesis, and biological characterization of cedazuridine and highlights the key role played by chemists in the process of drug discovery and development.