SGI-1027 is a DNMT inhibitor with IC50 of 6, 8, 7.5 μM for DNMT1, DNMT3A, and DNMT3B in cell-free assays, respectively.
Potential for use in epigenetic cancer therapy.
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.
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
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.
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.
GENERAL STEPS: 4-(quinolin-4-ylamino)benzoic acid (45 mg, 0.17 mmol) and N4-(4-aminophenyl)-6-methylpyrimidine-2,4-diamine (37 mg, 0.17 mmol) were dissolved in DMF (1.7 mL). Subsequently, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.06 g, 0.34 mmol) and 1-hydroxybenzotriazole hydrate (0.03 g, 0.17 mmol) were added sequentially. The reaction mixture was stirred at 65oC for 24 hours. After completion of the reaction, the solvent was removed by vacuum concentration and the residue was purified by column chromatography (silica gel, eluent ratio 85:13:2 dichloromethane/methanol/triethylamine) to afford N-[4-[(2-amino-6-methyl-4-pyrimidinyl)amino]phenyl]-4-(4-quinolinylamino)benzamide (0.05 g, 59% yield) as an amorphous yellow solid.
[1] JHARNA DATTA. A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation.[J]. ACS Chemical Health & Safety, 2009: 4277-4285. DOI:
10.1158/0008-5472.can-08-3669[2] LIVIUS PENTER. A rapid screening system evaluates novel inhibitors of DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk neuroblastoma.[J]. Targeted Oncology, 2015, 10 4: 523-533. DOI:
10.1007/s11523-014-0354-5[3] XUAN YANG . Discovery of the first chemical tools to regulate MKK3-mediated MYC activation in cancer[J]. Bioorganic & Medicinal Chemistry, 2021, 45: Article 116324. DOI:
10.1016/j.bmc.2021.116324
