1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers,Journal of Medicinal Chemistry

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1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00104
Aleksandra Twarda-Clapa ₁ , Sylwia Krzanik ₁ , Katarzyna Kubica ₂ , Katarzyna Guzik ₂ , Beata Labuzek ₂ , Constantinos G. Neochoritis ₃ , Kareem Khoury ₃ , Kaja Kowalska ₄ , Miroslawa Czub ₂ , Grzegorz Dubin _{1,

5} , Alexander Dömling ₃ , Lukasz Skalniak ₂ , Tad A. Holak _{2,

4,

5}

Affiliation

The tumor suppressor protein p53, the “guardian of the genome”, is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53–MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53–MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53–MDM2/MDMX inhibitors and conjugation with bioactive carriers.

中文翻译：

1,4,5-三取代咪唑基的p53–MDM2 / MDMX拮抗剂与脂肪族连接基与生物载体结合。

肿瘤抑制蛋白p53是“基因组的守护者”，在几乎所有类型的癌症中，TP53基因的突变或其负调控因子癌蛋白MDM2 / MDMX的过表达都会使其失活。通过使用小分子拮抗剂破坏p53–MDM2 / MDMX相互作用来恢复p53功能，可以提供一种有效的非基因毒性抗癌治疗方法。在这里，我们介绍了基于1,4,5-三取代的咪唑支架的p53–MDM2 / MDMX抑制剂的合成，活性和晶体结构，这些抑制剂附加有脂肪族连接基，可与生物活性载体偶联。该化合物在生化和细胞水平上均具有有利的性能。最有效的化合物19MMP2是MDM2的紧密结合物，可激活表达野生型p53的癌细胞中的p53，从而导致细胞周期停滞和生长抑制。晶体结构表明，化合物19通过脂肪族连接子诱导MDM2二聚化。这种独特的二聚结合模式为优化p53–MDM2 / MDMX抑制剂以及与生物活性载体结合开辟了新的前景。

更新日期：2017-05-17

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