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Resistance to clinical anti-androgens is an ongoing problem in the treatment of castration-resistant prostate cancer (CRPC). Although second generation anti-androgens demonstrate initial clinical benefit, patients often develop resistance to these therapies, evidenced by rising serum PSA levels and disease progression. Several mechanisms including the expression of androgen receptor (AR) splice variants contribute to the reactivation of AR signaling in drug-resistant prostate cancer. Novel therapies that target AR signaling and suppress growth in castration-resistant and anti-androgen-resistant prostate cancer are essential for the effective management of advanced disease. We developed a synthetic small molecule analog of mahanine, SH-I-125, a compound with the ability to disrupt androgen receptor signaling and induce apoptosis in castration-resistant and drug-resistant prostate cancer cellular models. SH-I-125 disrupted AR signaling and induced apoptosis in CRPC cells and anti-androgen-resistant prostate cancer cells in a manner more effective than clinical anti-androgens, enzalutamide and ARN509. Furthermore, SH-I-125 decreased full-length AR and its splice variant AR-V7 levels in 22Rv1 prostate cancer cells by a proteasome-dependent mechanism. These findings indicate the therapeutic potential of SH-I-125 in prostate cancer patients that have progressed on currently approved therapies for CRPC.