A new phenothiazine derivative inhibits human cancer through targeting master gene PELP1

Background/Objectives : Master gene locates on the key nodes of many signaling pathways implicating in many kinds of physiology and pathology conditions. PELP1 has been demonstrated to be a master gene and oncogene. However, target therapy to PELP1 is lack. Our aim is to find a new compound that has the potential to bind and specifically target to PELP1. Methods : In this study, a new phenothiazine derivative was synthesized using a phenothiazine basic bone and a targeting mitochondria cationic structure. Its anti-cancer effect was assessed in many tumor cell lines in vitro and the action mechanism was explored. Results: Compound A, a novel phenothiazine derivative, selectively targets mitochondria in cancer cells, inhibiting survival, migration, invasion, and colony formation while inducing apoptosis (not autophagy). It downregulates PELP1, suppressing PI3K/AKT/mTOR signaling, as confirmed by molecular docking and siRNA. PELP1 activation via saRNA partially reverses Compound A's effects. This highlights its potential as a targeted anticancer agent. Conclusions: In short, compound A, a new phenothiazine derivative can inhibit malignant biological behaviour of human cancer through targeting master gene PELP1.