DNMT-IN-6

DNMT-IN-6 is a DNA methyltransferase inhibitor effective against DNMT1, DNMT3A, and DNMT3B. It promotes demethylation and restores the expression of the TMS1 tumor suppressor gene. DNMT-IN-6 induces apoptosis, causes G2/M phase arrest, disrupts mitochondrial integrity, and activates endogenous caspase cascades (3/7/9). Additionally, it inhibits tumor growth and enhances survival rates in xenograft models. DNMT-IN-6 is applicable in cancer research, including studies on diffuse large B-cell lymphoma.

DNMT-IN-6 (Compound CZ2) at concentrations ranging from 0.2 to 1.4 μM for 24-48 hours, effectively and dose- and time-dependently inhibits the proliferation of SUDHL-4, SUDHL-6, and DB diffuse large B-cell lymphoma (DLBCL) cell lines, with IC50 values at 24 hours of 0.67 μM, 0.72 μM, and ~0.90 μM, respectively, while showing minimal cytotoxicity to normal HK-2 and MIN-6 cells. At a concentration of 1 μM for 24 hours, DNMT-IN-6 induces mitochondrial membrane depolarization in SUDHL-4 and SUDHL-6 DLBCL cells, significantly induces their apoptosis, and activates caspase-3 and caspase-9. Additionally, it reduces ATP levels and causes G2/M phase cell cycle arrest in SUDHL-6 DLBCL cells. DNMT-IN-6 also decreases the methylation level of the TMS1 promoter, upregulates TMS1 expression, and downregulates the expression of DNMT1, DNMT3A, and DNMT3B in SUDHL-4 and SUDHL-6 DLBCL cells. It inhibits the binding of DNMT3A to the TMS1 promoter in SUDHL-4 DLBCL cells, thus promoting demethylation of the TMS1 promoter.

DNMT-IN-6 (Compound CZ2) administered at 3.5 mg/kg via intraperitoneal injection every other day for a total of 12 days achieves a 71.39% tumor growth inhibition rate in BALB/c nude mice with SUDHL-4 DLBCL xenografts. It reduces tumor weight, extends survival, and modulates the TMS1/DNMT3A axis, while demonstrating a favorable safety profile.