对当前标准治疗（例如雄激素受体（AR）靶向治疗）产生耐药性仍然是晚期前列腺癌治疗中的主要挑战。迫切需要针对关键耐药驱动因素（例如 AR-V7 等 AR 变体和 AKR1C3 等类固醇生成酶）的治疗策略，以改善晚期前列腺癌患者的预后。在这里，我们设计、合成并表征了一类针对 AR/AR 变体和 AKR1C3 的 LX 化合物。分子对接表明 LX 化合物与 AKR1C3 活性位点结合。 LX1 阻断 AKR1C3 酶活性，抑制雄烯二酮转化为睾酮。 LX 化合物还降低 AR/AR-V7 表达并下调其靶基因。在体外，LX1 抑制对抗雄激素（包括恩杂鲁胺、阿比特龙、阿帕鲁胺和达洛鲁胺）耐药的前列腺癌细胞的生长。体内 LX1 治疗显着降低了肿瘤生长，降低了血清 PSA 水平，并降低了瘤内睾酮水平，且不影响小鼠体重。此外，LX1克服了对恩杂鲁胺治疗的耐药性，并且LX1与恩杂鲁胺的组合进一步抑制了肿瘤生长。总的来说，LX1 在减少瘤内睾酮和 AR 信号传导方面的双重作用，及其与耐药模型中标准疗法的协同作用，强调了其作为晚期前列腺癌有价值的治疗选择的潜力。

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate cancer. Here, we designed, synthesized, and characterized a class of LX compounds targeting both AR/AR variants and AKR1C3. Molecular docking indicated that LX compounds bound to the AKR1C3 active sites. LX1 blocked AKR1C3 enzymatic activity, suppressing the conversion of androstenedione into testosterone. LX compounds also reduced AR/AR-V7 expression and downregulated their target genes. In vitro, LX1 inhibited the growth of prostate cancer cells resistant to antiandrogens, including enzalutamide, abiraterone, apalutamide, and darolutamide. Treatment with LX1 in vivo significantly decreased tumor growth, lowered serum PSA levels, and reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 overcame resistance to enzalutamide treatment, and the combination of LX1 with enzalutamide further suppressed tumor growth. Collectively, the dual effect of LX1 in reducing intratumoral testosterone and AR signaling, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.