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Updated: Jan 3, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
Marc Aragó1, Juan Moreno-Felici1, Sonia Abás2
1Department of Physiological Sciences, School of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Spain.
Background:
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued.
Methods:
A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts.
Results:
Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity.
Conclusion:
We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.
Insights
A novel compound, iPEPCK-2, effectively inhibits PEPCK-M, a key enzyme in cancer cell metabolism. This targeted approach shows promise in reducing tumor growth without apparent toxicity.
Area of Science:
- Biochemistry
- Cancer Biology
- Drug Discovery
Background:
- Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is upregulated in cancer cells, aiding nutrient stress adaptation.
- Targeting PEPCK-M represents a novel therapeutic strategy for cancer treatment.
Purpose of the Study:
- To synthesize and evaluate a novel inhibitor, iPEPCK-2, targeting PEPCK-M.
- To assess the in vitro and in vivo efficacy of iPEPCK-2 in preclinical cancer models.
Main Methods:
- Synthesis of a 3-alkyl-1,8-dibenzylxanthine derivative (iPEPCK-2).
- In silico modeling, in vitro kinetic assays, and cellular thermal shift assays (CETSA) for potency and target engagement.
- Validation in cell-based assays and murine xenograft models.
Main Results:
- iPEPCK-2 demonstrated enhanced potency and cross-inhibitory capacity compared to existing compounds.
- The inhibitor suppressed cancer cell growth and survival, particularly under nutrient-deprived conditions, impacting colony formation.
- Daily administration of iPEPCK-2 significantly inhibited tumor growth in xenograft models without observable toxicity.
Conclusions:
- iPEPCK-2 is a potent anticancer agent targeting PEPCK-M.
- This inhibitor effectively targets a crucial metabolic adaptation pathway in tumors.
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