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Ref Type Journal Article
PMID (19417133)
Authors Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG, Phiasivongsa P, Redkar S, Jacob ST
Title A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation.
Journal Cancer research
Vol 69
Issue 10
Date 2009 May 15
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SGI-1027 SGI-1027 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SGI-1027 SGI 1027 DNMT inhibitor (Pan) 5 SGI-1027 binds and inhibits DNMT1, DNMT3A, and DNMT3B, which leads to decreased DNA methylation and may result the activation of silenced tumor suppressor genes (PMID: 19417133, PMID: 30344731).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable SGI-1027 Preclinical - Cell culture Actionable In a preclinical study, SGI-1027, inhibited DNA methylation and reactivated silenced tumor suppressor genes, and induced DNMT1 degradation in a variety of cancer cell lines in culture (PMID: 19417133). 19417133
Unknown unknown hepatocellular carcinoma not applicable SGI-1027 Preclinical - Cell culture Actionable In a preclinical study, treatment with SGI-1027 reduced proliferation of a rat hepatoma cell line in culture in culture (PMID: 19417133). 19417133