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5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors.

ABSTRACT: A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 ?M against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.

SUBMITTER: Xiang P

PROVIDER: S-EPMC6272711 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors.

Xiang Pu P Jie Hui H Zhou Yang Y Yang Bo B Wang Hui-Juan HJ Hu Jing J Hu Jian J Yang Sheng-Yong SY Zhao Ying-Lan YL

Molecules (Basel, Switzerland) 20150427 5

A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the ...[more]

PMID: 25923513

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Project description:Ectonucleotidases inhibitors (ENPPs, e5'NT (CD73) and h-TNAP) are potential therapeutic candidates for the treatment of cancer. Adenosine, the cancer-developing, and growth moiety is the resultant product of these enzymes. The synthesis of small molecules that can increase the acidic and ionizable structure of adenosine 5-monophosphate (AMP) has been used in traditional attempts to inhibit ENPPs, ecto-5'-nucleotidase and h-TNAP. In this article, we present a short and interesting method for developing substituted indole acetic acid sulfonate derivatives (5a-5o), which are non-nucleotide based small molecules, and investigated their inhibitory potential against recombinant h-ENPP1, h-ENPP3, h-TNAP, h-e5'NT and r-e5'NT. Their overexpression in the tumor environment leads to high adenosine level that results in tumor development as well as immune evasion. Therefore, selective, and potent inhibitors of these enzymes would be expected to decrease adenosine levels and manage tumor development and progression. Our intended outcome led to the discovery of new potent inhibitors like' 5e (IC50 against h-ENPP1 = 0.32 ± 0.01 μM, 58 folds increased with respect to suramin), 5j (IC50 against h-ENPP3 = 0.62 ± 0.003 μM, 21 folds increase with respect to suramin), 5c (IC50 against h-e5'NT = 0.37 ± 0.03 μM, 115 folds increase with respect to sulfamic acid), 5i (IC50 against r-e5'NT = 0.81 ± 0.05 μM, 95 folds increase with respect to sulfamic acid), and 5g (IC50 against h-TNAP = 0.59 ± 0.08 μM, 36 folds increase with respect to Levamisole). Molecular docking studies revealed that inhibitors of these selected target enzymes induced favorable interactions with the key amino acids of the active site, including Lys255, Lys278, Asn277, Gly533, Lys528, Tyr451, Phe257, Tyr340, Gln465, Gln434, Lys437, Glu830, Cys818, Asn499, Arg40, Phe417, Phe500, Asn503, Asn599, Tyr281, Arg397, Asp526, Phe419 and Tyr502. Enzyme kinetic studies revealed that potent compounds such as 5j and 5e blocked these ectonucleotidases competitively while compounds 5e and 5c presented an un-competitive binding mode. 5g revealed a non-competitive mode of inhibition.

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5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors.

Publications

5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors.

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