Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer.

Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound CD-15, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, CD-15 displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of CD-15. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of CD-15 in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that CD-15 covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, CD-15 exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, CD-15 emerges as a promising candidate for the treatment of PCa and deserves further investigation.