guadecitabine

Guadecitabine, also known as SGI-110, is a hypomethylating prodrug of decitabine used in the development of hematologic malignancies. It is designed to resist rapid degradation by cytidine deaminase and to provide prolonged exposure to decitabine, aiming to enhance inhibition of DNA methyltransferase and antineoplastic activity. Chemically, guadecitabine is described as a dinucleotide prodrug in which decitabine is linked to deoxyguanosine via a phosphodiester bond. After subcutaneous administration, it is converted to decitabine, which is phosphorylated and incorporated into DNA to reduce DNA methylation and reactivate silenced genes.

Clinical development has evaluated guadecitabine in adults with myelodysplastic syndromes, chronic myelodysplastic/myeloproliferative neoplasms, and acute myeloid leukemia, including both untreated and relapsed/refractory populations, as a single agent and in combination regimens. It has been studied in comparisons with standard hypomethylating therapies and across various dosing schedules intended to optimize drug exposure. Adverse events are consistent with cytotoxic and hypomethylating regimens and commonly include cytopenias, fatigue, nausea, fever, and infection risk; hepatic and renal events have been reported rarely. Pharmacokinetic studies indicate longer decitabine exposure with guadecitabine than with decitabine alone, with dose-proportional exposure and a relatively extended terminal half-life.

Regulatory status: Guadecitabine has not received approval from major agencies such as the U.S. Food and Drug Administration or the European Medicines Agency. Development continues in clinical trials to clarify its efficacy and safety profile in hematologic malignancies.