体外研究
NSC232003, a uracil derivative freely available by the NCI/DTP repository, provides a versatile lead for developing highly potent and cell-permeable UHRF1 inhibitors that will enable dissection of DNA methylation inheritance. NSC232003 is indeed an effective DNA methylation inhibitor and indicate that this particular nucleotide scaffold could provide a versatile basis for the design of potent UHRF1 inhibitors. NSC232003 is predicted to be partially deprotonated at pH 7, as the pK a of the more acidic imide nitrogen of the pyrimidine ring is a value of 7.6 in NSC232003. The DNMT1/UHRF1 interactions are significantly reduced after 4 h of incubation of U251 glioma cells with the most potent compound NSC232003, showing a 50% interaction inhibition at 15 μM as well as induction of global DNA cytosine demethylation as measured by ELISA.
