Structure-Guided Design of 7‑Azaindole DNMT1 Inhibitors Active Against Hypomethylating Agent‑Resistant Acute Myeloid Leukemia

However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Non-nucleoside, DNA methyltransferase 1 (DNMT1)-selective inhibitors offer a promising alternative.

To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7‑azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust anti-leukemic effects and favorable tolerability.