Parthenolide Derivatives as PKM2 Activators Showing Potential in Colorectal Cancer

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme overexpressed in colorectal cancer (CRC), supporting tumor energy and biosynthesis.
• Targeting PKM2 offers a potential therapeutic strategy for CRC treatment.

Purpose of the Study:

• To design and synthesize novel parthenolide (PTL) derivatives targeting PKM2.
• To evaluate the antiproliferative activity and mechanism of action of the lead compound 29e against CRC cells.

Main Methods:

• Structure-based design and stepwise optimization of PTL derivatives.
• In vitro assays to determine PKM2 inhibitory activity (AC50) and antiproliferative effects (IC50) on CRC cell lines (HT29, SW480).
• Western blotting to assess PKM2 expression and translocation, Seahorse analysis for metabolic activity (OCR, ECAR), and in vivo xenograft studies.

Main Results:

• Compound 29e demonstrated potent PKM2 inhibition (AC50 = 86.29 nM) and significant antiproliferative activity against HT29 (IC50 = 0.66 μM) and SW480 (IC50 = 0.22 μM) cells.
• 29e reduced total PKM2 expression, inhibited PKM2 dimer nuclear translocation, and suppressed the PKM2/STAT3 signaling pathway.
• Metabolically, 29e increased oxygen consumption rate (OCR) and decreased extracellular acidification rate (ECAR), indicating altered cellular respiration.
• The antiproliferative effect was dependent on PKM2, with Cys424 identified as the key binding site.
• In vivo, 29e significantly suppressed tumor growth in an HT29 xenograft model with no obvious toxicity.

Conclusions:

• Compound 29e is a potent PKM2 inhibitor with significant antiproliferative and tumor-suppressing effects in colorectal cancer models.
• 29e represents a promising drug candidate for CRC therapy, targeting PKM2 and its associated signaling pathways.