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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
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Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors

机译：取代的氧吲哚-3- ylidenes作为AMP-活化的蛋白激酶（AMPK）抑制剂

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AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：AMP活化蛋白激酶（AMPK）是一种中央代谢调节因子，促进缺氧下的癌症生长和存活，并在癌症干细胞的维持中发挥作用。询问癌症靶向AMPK潜力的主要挑战是缺乏有效和选择性的小分子抑制剂。化合物C已被广泛用作AMPK抑制剂，但它缺乏效力并且具有较差的选择性概况。多激酶抑制剂Sunitinib已经表现出效力的AMPK活性抑制作用，并且具有修饰的范围。在这里，我们设计并合成了几系列氧吲哚伞，以确定AMPK抑制的结构要求并改善选择性。我们鉴定了两种效率，新的氧吲哚基AMPK抑制剂，该抑制剂被设计成在AMPK的ATP结合位点与DFG基序相互作用，该关键特征避毒与瑞伊替尼的常见REFPTOR酪氨酸激酶靶标的相互作用。通过在髓性白血病细胞中抑制乙酰-CoA羧化酶（ACPK的已知底物，AMPK的已知底物，在髓性白血病细胞中抑制这些氧吲哚的细胞接合。有趣的是，尽管AMPK在K562细胞中高度表达并激活，但这些基于氧吲哚的AMPK抑制剂没有冲击细胞活力或导致显着的细胞毒性。我们的研究是具有治疗潜力的基于氧吲哚的AMPK抑制剂的进一步发展的平台。 （c）2020 Elsevier Masson SAS。版权所有。

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