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 6k . Employing techniques such as surface plasmon resonance (SPR) and molecular dynamics (MD) simulations, we have for the first time clearly demonstrated that 6k 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 in vitro and in vivo . The results show that compound 6k 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, 6k demonstrates favorable bioavailability and safety profiles, suggesting its promising potential for further development.