Reactivation of silenced tumor suppressor genes by 5-azacytidine (Vidaza) and 
its congener 5-aza-2'-deoxycytidine (decitabine) has provided an alternate 
approach to cancer therapy. We have shown previously that these drugs 
selectively and rapidly induce degradation of the maintenance DNA 
methyltransferase (DNMT) 1 by a proteasomal pathway. Because the toxicity of 
these compounds is largely due to their incorporation into DNA, it is critical 
to explore novel, nonnucleoside compounds that can effectively reactivate the 
silenced genes. Here, we report that a quinoline-based compound, designated 
SGI-1027, inhibits the activity of DNMT1, DNMT3A, and DNMT3B as well M. SssI 
with comparable IC(50) (6-13 micromol/L) by competing with S-adenosylmethionine 
in the methylation reaction. Treatment of different cancer cell lines with 
SGI-1027 resulted in selective degradation of DNMT1 with minimal or no effects 
on DNMT3A and DNMT3B. At a concentration of 2.5 to 5 micromol/L (similar to that 
of decitabine), complete degradation of DNMT1 protein was achieved within 24 h 
without significantly affecting its mRNA level. MG132 blocked SGI-1027-induced 
depletion of DNMT1, indicating the involvement of proteasomal pathway. Prolonged 
treatment of RKO cells with SGI-1027 led to demethylation and reexpression of 
the silenced tumor suppressor genes P16, MLH1, and TIMP3. Further, this compound 
did not exhibit significant toxicity in a rat hepatoma (H4IIE) cell line. This 
study provides a novel class of DNA hypomethylating agents that have the 
potential for use in epigenetic cancer therapy.