RETRACTED: A New Class of Quinoline-Based DNA Hypomethylating Agents Reactivates Tumor Suppressor Genes by Blocking DNA Methyltransferase 1 Activity and Inducing Its Degradation

Abstract

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. Sss I with comparable IC 50 (6-13 Mmol/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 Mmol/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. [Cancer Res 2009;69(10):4277-85]

RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

“…57,58 The current approach is to inhibit expression or hyperactivity of DNMT1. [59][60][61] However, demethylating agents lead to unavoidable non-specific genomic demethylation causing genomic instability, DNA damage, oncogene reactivation, and promote opportunities for cancer progression. [62][63][64][65] Because the RFTS domain functions as a key regulator of DNMT1 function, targeting RFTS interactions may revert euchromatin-associated DNMT1 activation while also normalizing pericentromeric DNA methylation.…”

DNA methylation in cancer

“…Today many are described, of different nature, but few are well characterized for their mechanism of action or their selectivity towards a specific DNMT (for review Fahy et al, 2012;Gros et al, 2012). For example, SGI-1027 belongs to a family of minor groove DNA binders developed by Denny and collaborators (Datta et al, 2009) and has been shown to inhibit DNA methylation in enzymatic tests and in cancer cells. We developed two families of DNMT inhibitors: procainamide conjugates that are selective of DNA methyltransferases versus histone methyltransferases and flavanoid derivatives that also inhibit DNA methylation in an in vivo model of zebrafish development (Ceccaldi et al, 2011).…”

Epigenetic aspects of MDS and its molecular targeted therapy

“…Hypomethylating agents show [71], and some potential in MDS [72]. Several studies are currently ongoing to obtain improved efficacies of these drugs, including the development of oral preparations [73] and small molecules that can inhibit DNMTs without requiring DNA incorporation [74]. The inhibition of histone-modifying enzymes will be another potential epigenetic target for MDS therapy.…”