As a vital kinase in the glycolysis system, PKM2 is extensively expressed in colorectal cancer (CRC) to support the energy and biosynthetic needs. In this study, we designed a series of parthenolide (PTL) derivatives through a stepwise structure optimization, and an excellent derivate 29e showed good activity on PKM2 (AC₅₀ = 86.29 nM) and displayed significant antiproliferative activity against HT29 (IC₅₀ = 0.66 μM) and SW480 (IC₅₀ = 0.22 μM) cells. 29e decreased the expression of total PKM2, prevented nucleus translocation of PKM2 dimer, and inhibited PKM2/STAT3 signaling pathway. 29e remarkably increased OCR and decreased the extracellular acidification rate (ECAR). The antiproliferative effect of 29e depended on PKM2, and the Cys424 of PKM2 was the key binding site. Furthermore, 29e significantly suppressed tumor growth in the HT29 xenograft model without obvious toxicity. These outcomes demonstrate that 29e is a promising drug candidate for the treatment of CRC.

中文翻译：

---

小白菊内酯衍生物作为 PKM2 激活剂在结直肠癌中显示出潜力

作为糖酵解系统中的重要激酶，PKM2 在结直肠癌 (CRC) 中广泛表达，以支持能量和生物合成需求。在本研究中，我们通过逐步结构优化设计了一系列小白菊内酯 (PTL) 衍生物，一种优异的衍生物29e对 PKM2 表现出良好的活性 (AC ₅₀ = 86.29 nM)，并对 HT29 表现出显着的抗增殖活性 (IC ₅₀ = 0.66 μM ) 和 SW480 (IC ₅₀ = 0.22 μM) 电池。29e降低了总PKM2的表达，阻止了PKM2二聚体的核转位，抑制了PKM2/STAT3信号通路。29e显着增加 OCR 并降低细胞外酸化率 (ECAR)。29e的抗增殖作用依赖于PKM2，PKM2的Cys424是关键结合位点。此外，29e在 HT29 异种移植模型中显着抑制肿瘤生长，且无明显毒性。这些结果表明，29e是治疗 CRC 的有希望的候选药物。