125
Gold(III) Metformin and Phenformin Prodrugs
Northwestern University
Small molecule
Oncology
Hit To Lead or Lead Optimization
• Metformin and phenformin target energy production in cancer cells by inhibiting Complex I of the mitochondrial respiratory chain, activating 5’- adenosine monophosphate-activated protein kinase (AMPK) and lowering body insulin levels by altering insulin/insulin-like growth factorI (I/IGF) pathway.
• Northwestern inventors designed a new series of AuIII complexes, featuring both energy-disrupting metformin or phenformin ligands and multitarget AuIII species.
• In vitro evidence demonstrated that metabolic changes caused by 3met initiated attempts of cancer cells to protect themselves by metabolic reprogramming, UPR and mitophagy. These defense processes were successfully prevented by shutdown of mitochondrial respiration and impairment of autophagic flux, leading to the inhibition of protein degradation and apoptotic cell death.
• High degree of selectivity of the novel complexes to cancer cells over healthy cells were observed. Lead drug candidate 3met halted the growth of aggressive breast tumors in a mammary fat pad breast cancer model and activated the immune response, indicating the potential benefits of this drug candidate for TNBC patients with high risk of metastasis and relapse.
WO2021194420A1
Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs. Angew Chem Int Ed Engl. (2021)
