Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer Cells,Journal of Medicinal Chemistry

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Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-02 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00176
Ludovic Halby ₁ , Yoann Menon ₁ , Elodie Rilova ₁ , Dany Pechalrieu ₁ , Véronique Masson ₁ , Celine Faux ₁ , Mohamed Amine Bouhlel ₂ , Marie-Hélène David-Cordonnier ₂ , Natacha Novosad ₁ , Yannick Aussagues ₁ , Arnaud Samson ₁ , Laurent Lacroix ₃ , Fréderic Ausseil ₁ , Laurence Fleury ₁ , Dominique Guianvarc’h ₄ , Clotilde Ferroud ₅ , Paola B. Arimondo _{1,

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Affiliation

Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly observed in cancer, and its inhibition by small molecules is promising for their reactivation. Here we designed bisubstrate analogues-based inhibitors, by mimicking each substrate, the S-adenosyl-l-methionine and the deoxycytidine, and linking them together. This approach resulted in quinazoline–quinoline derivatives as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. We highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group, and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of CDKN2A promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cell model system, we found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter, and the reactivation of a reporter gene.

中文翻译：

双底物类型类似物作为癌细胞中DNA甲基转移酶抑制剂的合理设计

在癌症中通常观察到肿瘤抑制基因启动子的异常DNA超甲基化，其被小分子抑制有望使其重新激活。在这里，我们通过模仿每个底物，S-腺苷-1-蛋氨酸和脱氧胞苷，并将它们连接在一起，设计了基于双底物类似物的抑制剂。这种方法导致喹唑啉-喹啉衍生物作为DNMT3A和DNMT1的有效抑制剂，有些表现出一定的同工型选择性。我们强调了（i）两个部分之间的连接抑制的重要性和刚性，因为（ii）在喹啉基团上存在氮，和（iii）在喹唑啉团上存在疏水基团。最有效的抑制剂诱导CDKN2A脱甲基结肠癌HCT116细胞中的启动子及其治疗7天后的活化。此外，在白血病细胞模型系统中，我们发现了由治疗诱导的启动子的去甲基化，启动子上的染色质打开和报告基因的重新激活之间的相关性。

更新日期：2017-05-24

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