Description
SGI-1027 is a DNMT inhibitor with IC50 of 6, 8, 7.5 μM for DNMT1, DNMT3A, and DNMT3B in cell-free assays, respectively.
Features
Potential for use in epigenetic cancer therapy.
In vitro
SGI-1027 inhibits DNA methylation by directly inhibiting DNMTs, and results in selective degradation of DNMT1 in a wide variety of human cancer cell lines. SGI-1027 exhibits minimal or no cytotoxic effect in rat hepatoma H4IIE cells. SGI-1027 (0-100 μM) exhibits a moderate pro-apoptotic effect on U937 human leukemia cell line with no relevant changes on the cell cycle.
Description
SGI-1027 (1020149-73-8) is a potent and selective inhibitor of DNA methyl transferase inhibiting DNMT1, DNMT3A and DNMT3B with comparable potency (IC50=12.5, 8.0 and 7.5 mM respectively).1? Treatment of various cancer cell lines with SGI-1027 results in selective degradation of DNMT1 (MG-132 sensitive) with minimal effect on DNMT3A and 3B at 2.5-5 mM.1 Prolonged treatment of RKO cells resulted in reexpression of silenced tumor suppressor genes.1 Synergizes with doxorubicin at growth inhibition in neuroblastoma cell lines.2 Disrupts the MKK3-MYC complex in cells and inhibits MYC transcriptional activity in colon and breast cancer cells.3
Uses
SGI-1027 is a quinoline derivative and a potent inhibitor of DNA methyltransferase (DNMT). SGI-1027 can be used as a potential therapeutic agent for the treatment of cancer and other diseases and also as a research tool to investigate the role of DNMTs in epigenetic events.
Biochem/physiol Actions
SGI-1027 is a DNA methyltransferase (DNMT) inhibitor with IC50 values of 6-13 μM for DNMT3B, DNMT3A and DNMT1. SGI-1027 directly inhibits DNMT activity by competing with the cofactor, S-adenosylmethionine (SAM) in the methylation reaction. SGI-1027 treatment of cancer cell lines induced degradation of DNMT1, but not DNMT3A or DNMT3B, and in RKO cells caused re-expression of the silenced tumor supressor genes p16, MLH1 and TIMP3.
References
Datta et al. (2009), A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation; Cancer Res., 69 4277
Penter et al. (2015) A rapid screening system evaluates novel inhibitors of DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk neuroblastoma; Target Oncol., 10 523
Yang et al. (2021), Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer; Bioorg. Chem., 45 116324
