Identification of Parthenolide Dimers as Activators of Pyruvate Kinase M2 in Xenografts of Glioblastoma Multiforme in Vivo.,Journal of Medicinal Chemistry

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Identification of Parthenolide Dimers as Activators of Pyruvate Kinase M2 in Xenografts of Glioblastoma Multiforme in Vivo.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-03 , DOI: 10.1021/acs.jmedchem.9b01328
Yahui Ding ₁ , Qingqing Xue ₁ , Shuo Liu ₁ , Kai Hu ₂ , Da Wang ₁ , Tianpeng Wang ₁ , Ye Li ₁ , Hongyu Guo ₁ , Xin Hao ₁ , Weizhi Ge ₁ , Yan Zhang ₁ , Ang Li ₁ , Jing Li ₁ , Yue Chen ₁ , Quan Zhang ₁

Affiliation

Herein we detail the discovery of a series of parthenolide dimers as activators of PKM2 and evaluation of their anti-GBM activities. The most promising compound 5 showed high potency to activate PKM2 with an AC50 value of 15 nM, inhibited proliferation and metastasis, and induced apoptosis of GBM cells. Compound 5 could promote tetramer formation of PKM2 and reduce nucleus translocation of PKM2 in GBM cells without influence on the expression of total PKM2, thereby inhibiting the STAT3 signal pathway in vitro and in vivo. PKM2 knockdown assay demonstrated that the anti-GBM effect of 5 mainly depended on the expression of PKM2 in vitro and in vivo. Compound 16, a prodrug of 5, markedly suppressed U118 tumor xenograft growth and reduced the weight of tumor. On the basis of these investigations, we propose that 16 might be considered as a promising lead compound for discovery of anti-GBM drugs.

中文翻译：

鉴定为多形性胶质母细胞瘤异种移植物中丙酮酸丙酮酸激酶M2激活剂的小白菊内酯二聚体。

在本文中，我们详细介绍了一系列作为PKM2激活剂的酚类二聚体的发现及其抗GBM活性的评估。最有前途的化合物5表现出以15 nM的AC50值激活PKM2的高效能，抑制增殖和转移，并诱导GBM细胞凋亡。化合物5可以促进GBM细胞中PKM2的四聚体形成并减少PKM2的核易位，而不影响总PKM2的表达，从而在体外和体内抑制STAT3信号通路。PKM2敲低分析表明5的抗GBM作用主要取决于体外和体内PKM2的表达。化合物16（5的前药）显着抑制了U118肿瘤异种移植的生长并减轻了肿瘤的重量。根据这些调查，

更新日期：2020-02-03

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