PeS-9 is an androgen receptor (AR) degrader that induces the degradation of androgen receptors. It enhances the production of cytotoxic reactive oxygen species (ROS), leading to mitochondrial and endoplasmic reticulum stress, which results in the release of mitochondrial cytochrome C and AIF. PeS-9 activates caspase-9 and caspase-3, causing DNA fragmentation and apoptosis. It exhibits anti-prostate cancer activity and demonstrates antitumor and antimetastatic effects in vivo with minimal side effects. PeS-9 is applicable for targeted therapy research in GLUT-1 overexpressing tumors.

PeS-9 exhibits cytotoxicity in cancer cells with IC 50 values of 0.49 μM (DU145) and 0.58 μM (LNCaP), while displaying lower cytotoxicity in non-cancer cells with IC 50 values of 3.41 μM (PNT2), 3.53 μM (MRC-9), 11.7 μM (HUVEC), and 7.51 μM (HEK). PeS-9 (0-2.5 μM, 4-48 h) downregulates the AR signaling pathway in 22Rv1 cells, induces ROS production, and causes DNA damage. It demonstrates synergistic effects with the anti-androgen drug Enzalutamide and the PARP inhibitor Olaparib in prostate cancer cells, with CI < 0.75. PeS-9 (0-1 μM, 1 h) activates the MAPK signaling pathway by increasing stress kinase levels p-p38, p-JNK, and p-ERK in 22Rv1 cells, an effect that is antagonized by MAPK inhibitors. Through targeting mitochondria and inducing ROS, PeS-9 (0-2.5 μM, 1-48 h) triggers apoptosis in 22Rv1 cells. It elevates cytosolic Ca2+ levels, causes ER expansion, alters mitochondrial membrane permeability, and induces DNA damage, quantified by increased sub-G1 cell populations. Additionally, PeS-9 (0.5-4 μM, 24 h) inhibits glucose uptake in 22Rv1 cells, and this effect is suppressed by the GLUT-1 inhibitor Phloretin. Moreover, PeS-9 (0.1-10 μM, every 5 days over 20 days) dose-dependently reduces the survival fraction of tumor spheroids.

PeS-9 (27.9 mg/kg, i.p., daily for 15 days) demonstrates in vivo anti-tumor and anti-metastatic properties with minimal side effects in NSG mice with 22RV1 subcutaneous xenografts.