Development of the First YTHDC1 Degrader with Improved Antileukemia Activity.

N6-Methyladenosine (m6A) represents the most prevalent internal RNA modification in eukaryotic mRNA, with YTHDC1 serving as a critical nuclear reader protein implicated in acute myeloid leukemia (AML). Although selective inhibitors of YTHDC1 have been reported, whether targeted degradation of YTHDC1 could achieve enhanced therapeutic efficacy remains unexplored. Here, we report the rational design and synthesis of the first PROTAC molecule targeting YTHDC1, termed XY-2, which was developed based on the cocrystal structure of YTHDC1 bound to its known inhibitor. XY-2 efficiently induced proteasome-dependent degradation of YTHDC1 at low nanomolar concentrations, with DC50 values of 11.42 nM in MOLM13 and 13.59 nM in Kasumi-1 cells. Functionally, XY-2 markedly inhibited proliferation, migration, and invasion, while robustly promoting apoptosis in multiple AML cell lines, with superior potency compared to its parent inhibitor. Transcriptomic and mechanistic analyses revealed that XY-2 downregulated genes associated with cell cycle, DNA replication, and mitotic progression, leading to G1 phase arrest. These findings establish XY-2 as the first highly efficient degrader of YTHDC1 and highlight targeted degradation of YTHDC1 as a promising therapeutic strategy for AML.