DNMT1 Degrader-1 is a selective DNMT1 degrader with an IC50 of 202.87 nM and a Kd value of 122 nM. As a molecular glue, DNMT1 Degrader-1 forms a ternary complex with DNMT1 and UHRF1, thereby triggering UHRF1 -mediated ubiquitination and degradation of DNMT1, and inhibiting the enzymatic activity of DNMT1. DNMT1 Degrader-1 inhibits the proliferation of primary acute myeloid leukemia cells and exerts anti-tumor activity. DNMT1 Degrader-1 can be used for the research of acute myeloid leukemia [1].
In Vivo, DNMT1 Degrader-1 (40 mg/kg; i.p.; once daily; for 16 consecutive days) significantly inhibits the growth of acute myeloid leukemia and prolongs survival in MV‑4‑11 cell-derived xenograft, WEHI‑3 orthotopic transplantation, and acute myeloid leukemia (AML) patient-derived xenograft mouse models[1]. DNMT1 Degrader-1 (40 mg/kg; i.p.; daily administration; consecutive 14 days) exhibits extremely low in vivo hematological toxicity in healthy BALB/c mice following 14 days of daily intraperitoneal injection[1].
In Vitro, DNMT1 Degrader-1 (compound 6k) (0-2000 nM; 0-24 h) induces time- and concentration-dependent degradation of DNMT1 protein in MV-4-11 acute myeloid leukemia (AML) cells, with a DC50 of 123.4 nM[1]. DNMT1 Degrader-1 (0.25-1 μM; 24 h) does not affect DNMT1 mRNA levels in Kasumi-1 or MV-4-11 AML cells[1]. DNMT1 Degrader-1 (1 μM; 6 h) induces ubiquitination of DNMT1 protein in MV-4-11 acute myeloid leukemia (AML) cells, thereby leading to its proteasomal degradation[1]. The effect of DNMT1 Degrader-1 (1 μM; 0-24 h) on inducing ubiquitination and degradation of DNMT1 in MV-4-11 acute myeloid leukemia (AML) cells is dependent on UHRF1[1]. DNMT1 Degrader-1 (72 h) inhibits the proliferation of various AML and hematological cancer cell lines[1]. DNMT1 Degrader-1 (0.2-2 μM; 24 h) induces dose-dependent cell cycle arrest in MV-4-11 and Kasumi-1 acute myeloid leukemia (AML) cells[1].
References:
[1]. Ma L, et al. Discovery of a Selective DNMT1 Degrader with a Unique Molecular Glue Mechanism as a Potential Therapeutic Agent for Acute Myeloid Leukemia. J Med Chem. 2026;69(7):7756-7781.
In Vivo, DNMT1 Degrader-1 (40 mg/kg; i.p.; once daily; for 16 consecutive days) significantly inhibits the growth of acute myeloid leukemia and prolongs survival in MV‑4‑11 cell-derived xenograft, WEHI‑3 orthotopic transplantation, and acute myeloid leukemia (AML) patient-derived xenograft mouse models[1]. DNMT1 Degrader-1 (40 mg/kg; i.p.; daily administration; consecutive 14 days) exhibits extremely low in vivo hematological toxicity in healthy BALB/c mice following 14 days of daily intraperitoneal injection[1].
In Vitro, DNMT1 Degrader-1 (compound 6k) (0-2000 nM; 0-24 h) induces time- and concentration-dependent degradation of DNMT1 protein in MV-4-11 acute myeloid leukemia (AML) cells, with a DC50 of 123.4 nM[1]. DNMT1 Degrader-1 (0.25-1 μM; 24 h) does not affect DNMT1 mRNA levels in Kasumi-1 or MV-4-11 AML cells[1]. DNMT1 Degrader-1 (1 μM; 6 h) induces ubiquitination of DNMT1 protein in MV-4-11 acute myeloid leukemia (AML) cells, thereby leading to its proteasomal degradation[1]. The effect of DNMT1 Degrader-1 (1 μM; 0-24 h) on inducing ubiquitination and degradation of DNMT1 in MV-4-11 acute myeloid leukemia (AML) cells is dependent on UHRF1[1]. DNMT1 Degrader-1 (72 h) inhibits the proliferation of various AML and hematological cancer cell lines[1]. DNMT1 Degrader-1 (0.2-2 μM; 24 h) induces dose-dependent cell cycle arrest in MV-4-11 and Kasumi-1 acute myeloid leukemia (AML) cells[1].
References:
[1]. Ma L, et al. Discovery of a Selective DNMT1 Degrader with a Unique Molecular Glue Mechanism as a Potential Therapeutic Agent for Acute Myeloid Leukemia. J Med Chem. 2026;69(7):7756-7781.