Discovery of a Selective DNMT1 Degrader with a Unique Molecular Glue Mechanism as a Potential Therapeutic Agent for Acute Myeloid Leukemia

Previous research indicated that DNA methyltransferase 1 (DNMT1) inhibitors can induce UHRF1-mediated degradation of the DNMT1 protein. However, the underlying degradation mechanism remains poorly understood. During our investigation of a series of quinazoline-based DNMT1 inhibitors, we serendipitously discovered a highly potent and selective DNMT1 degrader <b>6k</b>. Employing techniques such as surface plasmon resonance (SPR) and molecular dynamics (MD) simulations, we have for the first time clearly demonstrated that <b>6k</b> can promote a significant direct interaction between DNMT1 and UHRF1 proteins via a molecular glue mechanism under cell-free conditions. Further biological evaluations indicated that this DNMT1 degrader exhibits potent inhibitory effects on AML cells both <i>in vitro</i> and <i>in vivo</i>. The results show that compound <b>6k</b> effectively suppresses the proliferation of primary AML cells and significantly extends the survival of experimental animals in the patient-derived xenograft (PDX) model. More importantly, <b>6k</b> demonstrates favorable bioavailability and safety profiles, suggesting its promising potential for further development.