SGI-1027

SGI-1027 is an inhibitor of DNMT with IC50 values of 12.5μM, 8μM and 7.5μM, respectively for DNMT1, DNMT3A and DNMT3B [1].

SGI-1027 shows inhibition with mammalian DNMTs and bacterial M. SssI in vitro. Both the endogenous and recombinant DNMTs can be inhibited by SGI-1027. The mechanism of this inhibition is that SGI-1027 competes with Ado-Met but not the substrate DNA within the cofactor binding site of the enzyme. SGI-1027 inhibits DNA methylation through directly inhibiting DNMTs [1].

In cancer cells, many TSGs are silenced due to hypermethylation of CpG islands in their promoters. SGI-1027 can demethylates these CpG islands and reactivate the silenced TSGs. In RKO cells, prolonged treatment of SGI-1027 induces reexpression of P16 and TIMP3 genes. Moreover, SGI-1027 is found to cause selective degradation of DNMT1 via proteasomal pathway [1].

References:
[1] Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG, Phiasivongsa P, Redkar S, Jacob ST. 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. 2009 May 15;69(10):4277-85.

Synthetic approaches to DNMT inhibitor SGI-1027 and effects on the U937 leukemia cell line.[Pubmed:23402879]

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1631-5.

The known DNMT inhibitor SGI-1027 4 has been synthesized using as key steps Pd-catalyzed Ar-N bond formation reactions performed in a sequential or convergent manner. In the former approach, a by-product, which corresponds to the incorporation of two units of 4-chloroquinoline, was also isolated. The biological effects of compound 4 in the U937 human leukemia cell line are also described.

Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.[Pubmed:23637988]

PLoS One. 2013 Apr 25;8(4):e62152.

DNA methylation is an epigenetic modification that regulates gene expression by DNA methyltransferases (DNMTs). Inhibition of DNMTs is a promising approach for cancer therapy. Recently, novel classes of the quinolone-based compound, SGI-1027, and RG108-procainamide conjugates, CBC12, have been identified as potent DNMT inhibitors. In this work, we report comprehensive studies using induced-fit docking of SGI-1027 and CBC12 with human DNMT1 and DNMT3A. The docking was performed in the C-terminal MTase catalytic domain, which contains the substrate and cofactor binding sites, in the presence and absence of other domains. Induced-fit docking predicts possible binding modes of the ligands through the appropriate structural changes in the receptor. This work suggests a hypothesis of the inhibitory mechanisms of the new inhibitors which is in agreement with the reported autoinhibitory mechanism. The insights obtained in this work can be used to design DNMT inhibitors with novel scaffolds.

Design, synthesis and biological evaluation of 4-amino-N- (4-aminophenyl)benzamide analogues of quinoline-based SGI-1027 as inhibitors of DNA methylation.[Pubmed:24678024]

ChemMedChem. 2014 Mar;9(3):590-601.

Quinoline derivative SGI-1027 (N-(4-(2-amino-6-methylpyrimidin-4-ylamino)phenyl)-4-(quinolin-4-ylamino)benzamid e) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine-5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI-1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds-namely the derivatives 12, 16, 31 and 32-exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re-expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG-1 cells. These compounds possessed cytotoxicity against leukemia KG-1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI-1027. Structure-activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one-ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure-activity relationships of SGI-1027 and its derivative.

SGI-1027 is a DNA methyltransferase (DNMT) inhibitor, with IC50s of 7.5 μM, 8 μM, and 12.5 μM for DNMT3B, DNMT3A, and DNMT1 with poly(dI-dC) as substrate.

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