High-throughput screening to identify inhibitors of breast-to-brain metastasis

National Center For Advancing Translational Sciences

Investigators

Abstract

During this period, the collaborative research team performed efficacy testing using a combination approach that identified molecules with synergistic toxicity against brain-metastatic cells. The capacity of the compounds to cross the blood-brain-barrier was assessed using computational methods and in vitro PAMPA-BBB permeability assays. Non-desirable effects on non-cancer cells was examined using a normal mammary epithelium cell model. The team focused particular attention on a CNS-penetrant, pan-Erbb inhibitor poziotinib, which showed efficacy in murine models of brain metastasis. A compound class that was highly synergistic with poziotinib was advanced to pharmacokinetics studies, formulation studies, and efficacy studies. A chemical probe to identify targets of poziotinib was also synthesized.