| HRA014189
(Controlled Access)
|
Aberrant DNA hypermethylation silences tumor suppressor genes (TSGs) and contributes to the progression of both liquid and solid cancers, yet current DNA hypomethylating therapies are limited by toxicity and resistance. We introduce DMI46, a non-nucleoside, DNMT1-selective inhibitor featuring a 7-azaindole scaffold that potently reverses cancer-specific DNA hypermethylation and reactivates TSGs. Structural studies reveal enhanced intercalation and minor groove contacts that stabilize DNMT1 binding, supporting its sustained activity in cells resistant to the previous dicyanopyridine inhibitor. DMI46 restores sensitivity to nucleoside hypomethylating agents and displays robust anti-leukemic effects with favorable tolerability in preclinical models, presenting a promising new approach to overcome resistance and broaden epigenetic therapy options for acute myeloid leukemia. |
