Carboranylanilinoquinazoline EGFR-inhibitors: toward 'lead-to-candidate' stage in the drug-development pipeline.
Marcos CoutoCatalina AlamónCarina SánchezBelén DávilaMarcelo FernándezNicole LecotPablo CabralFrancesc TeixidorClara ViñasHugo E CerecettoPublished in: Future medicinal chemistry (2020)
Background: Carboranylanilinoquinazoline-hybrids, developed for boron neutron capture therapy, have demonstrated cytotoxicity against murine-glioma cells with EGFR-inhibition ability. In addition, their adequate aqueous/metabolic stabilities and ability to cross blood-brain barrier make them good leads as to become antiglioma drugs. Aim: Analyze drug-like properties of representative carboranylanilinoquinazolines. Materials & methods: To expand carboranylanilinoquinazolines therapeutic spectrum, we studied their ability to act against glioma-mammal cells, U-87 MG and other tyrosine kinase-overexpress cells, HT-29. Additionally, we predicted theoretically and studied experimentally drug-like properties, in other words, organization for economic cooperation and development-recommended toxicity-studies and, due to some aqueous-solubility problems, and vehicularization for oral and intravenous administrations. Conclusion: We have identified a promising drug-candidate with broad activity spectrum, appropriate drug-like properties, adequate toxicological behavior and able ability to be loaded in suitable vehicles.
Keyphrases
- tyrosine kinase
- blood brain barrier
- epidermal growth factor receptor
- induced apoptosis
- small cell lung cancer
- cell cycle arrest
- mental health
- adverse drug
- oxidative stress
- drug delivery
- ionic liquid
- endoplasmic reticulum stress
- high dose
- emergency department
- cerebral ischemia
- brain injury
- case control
- replacement therapy
- solid state
- smoking cessation
- pi k akt