Development of isoselenazolium chlorides as selective pyruvate kinase isoform M2 inhibitors

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Cancer cells exhibit altered metabolic pathways, presenting therapeutic targets.
• Pyruvate kinase M2 (PKM2) is crucial for cancer cell proliferation and glucose metabolism.
• Targeting PKM2 offers a strategy for selective tumor cell elimination.

Purpose of the Study:

• To design and characterize novel selective inhibitors of PKM2 as potential anti-cancer agents.
• To elucidate the mechanism of action of these novel PKM2 inhibitors.

Main Methods:

• Design and synthesis of novel isoselenazolium chlorides.
• In vitro enzymatic assays to determine PKM2 inhibitory activity (IC50).
• Analysis of PKM2 mRNA expression, mitochondrial function, and oxidative stress.
• Cytotoxicity assays against various cancer cell lines.

Main Results:

• A novel class of isoselenazolium chlorides were identified as selective PKM2 inhibitors.
• Compound 5c demonstrated potent inhibition with an IC50 of 0.35 ± 0.07 μM.
• Inhibition involved inducing a functionally deficient tetrameric assembly of PKM2 with competitive characteristics.
• Compound 5c downregulated PKM2 mRNA, modulated mitochondrial function, induced oxidative burst, and exhibited cytotoxicity across cancer types.

Conclusions:

• Isoselenazolium chlorides represent a new class of PKM2 inhibitors with a unique mechanism.
• These compounds show promise as anti-cancer therapeutics.
• The findings provide valuable tools for further investigation into PKM2's role in cancer.