Histone methyltransferase enzyme SET7 and mixed-lineage leukemia protein (MLL) complex are crucial co-activators of androgen receptor (AR) and have recently emerged as potential therapeutic targets for advanced castration-resistant prostate cancer (CRPC). In this study, we described the identification of a rhodium-based hybrid complex (SM_1) as a potent blocker of AR activity via simultaneously inhibiting SET7 and MLL complex activity, which makes it a potential lead scaffold for CPRC drug development.