New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Pyruvate kinase M2 (PKM2) plays a crucial role in the Warburg effect, a metabolic alteration characteristic of cancer cells.
• Targeting PKM2 offers a potential strategy for developing tumor-selective therapies due to its role in aberrant cancer metabolism.

Purpose of the Study:

• To discover and develop novel activators of PKM2 with potential anticancer activities.
• To investigate the structure-activity relationships of identified PKM2 activators and their therapeutic potential.

Main Methods:

• Random screening of an in-house compound library to identify initial PKM2 activators.
• Design, synthesis, and evaluation of lead compound analogs for PKM2 activation and anticancer effects.
• Molecular docking studies to elucidate structure-activity relationships.
• Preliminary pharmacological studies, including cell cycle analysis.

Main Results:

• Lead compound 8 was identified as a novel PKM2 activator.
• 7-Azaindole analog 32 emerged as the most potent PKM2 activator.
• Compounds demonstrated selective anti-proliferation activity against cancer cell lines (HCT116, Hela, H1299) but not a non-tumor cell line (BEAS-2B).
• Compound 32 was found to arrest the cell cycle at the G2/M phase in HCT116 cells.

Conclusions:

• Compound 32 is a potent PKM2 activator with selective anticancer properties.
• The identified compounds represent promising candidates for further development as targeted cancer therapeutics.
• Targeting PKM2 activation offers a viable strategy for cancer treatment by modulating cellular metabolism.