GSK3685032

**GSK3685032** is a first-in-class, potent, non-nucleoside, reversible, and highly selective small molecule inhibitor of **DNA methyltransferase 1 (DNMT1)**, an enzyme responsible for maintaining DNA methylation during cell division. GSK3685032 demonstrates specificity for DNMT1 over related methyltransferases (DNMT3A and DNMT3B), leading to robust DNA hypomethylation, activation of gene expression, and growth inhibition in a range of hematologic cancer cell lines, notably acute myeloid leukemia (AML). Unlike nucleoside hypomethylating agents (e.g., decitabine, azacytidine) that act by irreversible covalent inhibition and are associated with significant toxicity to normal blood cells, GSK3685032 competitively and reversibly inhibits DNMT1 by displacing its active-site loop from hemi-methylated DNA. Preclinical animal models indicate favorable pharmacokinetics and a superior safety profile compared to decitabine, with reduced myelosuppression and improved antitumor efficacy. Developed by GSK, this compound is a chemically optimized, high-throughput-screen-derived agent designed to provide a safer and more effective approach to targeting aberrant methylation in hematologic malignancies, especially AML[1][2][3][5][6][9].