6,8-bis-1-phenethylbiguanide-6,8-bis-thio-octanoic acid is a potent new bifunctional anticancer drug (abbreviated CPI-613-BBG) which has CPI-613 activity and simultaneously attacks the source of CPI-613 resistance

Background

Advanced carcinomas frequently exhibit rapid and nearly universal resistance to conventional therapies, including chemotherapy, kinase inhibitors, and immunotherapies, which typically rely on the induction of mitochondrial redox signaling to trigger cell death. A primary driver of this clinical failure is the metabolic upregulation of mitochondrial antioxidants, often fueled by lipid-derived reducing potential fluxing through the electron transport system, which effectively neutralizes the oxidative stress required for therapeutic efficacy. Even targeted metabolic inhibitors that disrupt the tricarboxylic acid (TCA) cycle by attacking enzymes such as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase face significant hurdles, as elevated antioxidant levels in resistant tumor cells quench the signals necessary for enzyme repression. Furthermore, while certain metabolic modifiers like biguanides show promise in disrupting these resistance mechanisms, their systemic administration is often limited by off-target toxicity in healthy tissues, highlighting a critical need for strategies that can overcome antioxidant-mediated resistance while maintaining tumor selectivity.

Technology

Researchers at Stony Brook University developed CPI-613 (or devimistat) -bis-biguanide (CPI-613-BBG), a bifunctional small molecule consisting of a CPI-613 backbone modified with two biguanide substituents. The CPI-613 component selectively accumulates in tumor mitochondria, where it inhibits the pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH) enzymes of the TCA cycle. The integrated biguanide groups target the mitochondrial electron transport system to suppress the production of mitochondrial antioxidants, which otherwise neutralize the redox signaling required for CPI-613 activity. By simultaneously disrupting TCA cycle metabolism and inhibiting the electron transport chain responsible for treatment resistance, the molecule enhances anti-tumor activity in resistant cell lines while limiting toxicity in normal tissues.

Advantages

• Overcomes resistance to devimistat (CPI-613)
• Eliminates normal tissue toxicity associated with standard biguanides
• Universal synergy with existing cancer therapies
• Streamlined bifunctional mechanism of action

Application

• Oncology therapeutics