Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein

DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1‐targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis‐targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50 = 643/899 nM in MV4‐11/MOLM‐13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1‐selective degradation in a dose‐ and time‐dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor‐suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1‐targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1‐related studies.