Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• AMP-activated protein kinase (AMPK) is a crucial metabolic regulator implicated in cancer progression and stem cell maintenance.
• Existing AMPK inhibitors like Compound C lack potency and selectivity, hindering therapeutic development.
• Sunitinib shows potent AMPK inhibition but targets multiple kinases, necessitating more selective agents.

Purpose of the Study:

• To design and synthesize novel oxindole-based compounds for potent and selective AMP-activated protein kinase (AMPK) inhibition.
• To elucidate the structural requirements for AMPK inhibition within the oxindole scaffold.
• To establish a foundation for developing novel AMPK-targeted cancer therapeutics.

Main Methods:

• Design and synthesis of multiple oxindole derivative series.
• Biochemical assays to assess AMPK inhibition and selectivity.
• Cellular assays using myeloid leukemia cells to confirm AMPK engagement via acetyl-CoA carboxylase (ACC) phosphorylation.
• Assessment of compound effects on cell viability and cytotoxicity.

Main Results:

• Identification of two novel, potent oxindole-based AMPK inhibitors.
• These inhibitors interact with the DFG motif of AMPK's ATP-binding site, enhancing selectivity.
• Cellular studies confirmed AMPK inhibition through reduced ACC phosphorylation in K562 cells.
• No significant impact on cell viability or cytotoxicity was observed in K562 cells despite high AMPK expression.

Conclusions:

• Novel oxindole-based compounds demonstrate potent and selective inhibition of AMPK.
• These inhibitors represent a promising scaffold for developing targeted cancer therapies.
• Further optimization is warranted to explore the therapeutic potential of these AMPK inhibitors.