<br>PKM2/PDK1 双靶向 shikonin 衍生物通过重塑葡萄糖代谢来恢复 EGFR 突变的 NSCLC 细胞对吉非替尼的敏感性,European Journal of Medicinal Chemistry

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PKM2/PDK1 双靶向 shikonin 衍生物通过重塑葡萄糖代谢来恢复 EGFR 突变的 NSCLC 细胞对吉非替尼的敏感性
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2023-01-29 , DOI: 10.1016/j.ejmech.2023.115166
Hongyan Lin ₁ , Hongwei Han ₂ , Minkai Yang ₂ , Zhongling Wen ₂ , Qingqing Chen ₃ , Yudi Ma ₃ , Xuan Wang ₃ , Changyi Wang ₃ , Tongming Yin ₄ , Xiaoming Wang ₃ , Guihua Lu ₂ , Hongyuan Chen ₅ , Jinliang Qi ₂ , Yonghua Yang ₂

Affiliation

丙酮酸激酶 2 （PKM2）和丙酮酸脱氢酶激酶 1 （PDK1）是肿瘤葡萄糖代谢途径中的两种关键酶，不仅通过加速有氧糖酵解促进肿瘤生长和增殖，还有助于非小细胞肺癌（NSCLC）的耐药性。考虑到单独靶向 PKM2 或 PDK1 似乎不足以重塑异常葡萄糖代谢以实现显着的抗肿瘤活性，我们提出了一种同步调节 PKM2 和 PDK1 的“两步法”。首先，我们发现 ML265 （PKM2 激活剂）和 AZD7545 （PDK1 抑制剂）的组合可以协同抑制 H1299 细胞的增殖并诱导细胞凋亡。基于此，我们设计了一系列新型紫草素（SK）硫醚衍生物作为 PKM2/PDK1 双靶点药物，其中最有效的化合物 E5 在苯环上具有 2-甲基取代，对 EGFR 突变型 NSCLC 细胞 H1975 的抑制活性显著提高（IC50 = 1.51 μmol/L），其活性分别是先导化合物 SK （IC50 = 4.56 μmol/L）和阳性对照吉非替尼（IC50 = 25.56 μmol/L）的 3 倍和 17 倍，分别。此外，E5 在异种移植小鼠模型中也显示出良好的抗肿瘤活性，毒性副作用显著低于 SK。此外，E5 还抑制 PKM2 进入细胞核以调节癌基因的转录激活，从而恢复 H1975 细胞对吉非替尼的敏感性。总的来说，这些数据表明，E5 是 PKM2/PDK1 的双重抑制剂，可能是吉非替尼治疗 EGFR-TKI 耐药 NSCLC 的一种很有前途的辅助药物，值得进一步研究。

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PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism

Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a “two-step approach” that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC50 = 4.56 μmol/L) and the positive control gefitinib (IC50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5, a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation.

更新日期：2023-01-29

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