Brexpiprazole

Brexpiprazole is a serotonin–dopamine activity modulator (SDAM) which is a partial agonist for the D2/D3 receptors and the 5-HT1A receptor and an antagonist for the 5-HT2A receptor. It has the same antipsychotic properties as aripiprazole, but with a different side effect profile. As a therapy for oncology, Brexpiprazole's mechanism of action is primarily through down-regulation of the anti-apoptotic protein survivin, which is important for maintaining CSC viability and resistance to EGFR TKIs. By decreasing survivin transcription, brexpiprazole lowers mitochondrial stability, leading to activation of caspase-dependent apoptosis, and sensitizes GSCs to osimertinib (a third-generation EGFR-TKI). The drug shows similar efficacy in both wild type EGFR and EGFRvIII positive cells, and this effect is independent of canonical EGFR downstream pathways. Pharmacologic inhibition or genetic knock-down of survivin recapitulates the chemosensitizing activity of brexpiprazole, thus confirming survivin as the relevant target.
In addition to Glioblastoma, this has also been shown to increase the efficacy of gemcitabine and 5-fluorouracil in pancreatic and non-small-cell lung cancer stem cells, making it a potentially broad-spectrum CSC-targeting adjuvant.

Fig. 1 Brexpiprazole sensitizes glioma stem cells to Osimertinib. (Suzuki S.; et al. 2019)