Department of Urologic Surgery, University of California Davis, Davis, California.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio.
Cancer Res. 2024 Nov 4;84(21):3617-3628. doi: 10.1158/0008-5472.CAN-24-0440.
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 new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo-keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and to inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide (Enza), abiraterone, apalutamide, and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to Enza treatment, and its combination with Enza further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR patient-derived xenograft models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer. Significance: LX1 simultaneously targets androgen receptor variants and the steroidogenic enzyme AKR1C3, offering a promising approach to combat drug resistance and enhancing therapeutic efficacy in conjunction with standard treatments for advanced prostate cancer.
当前标准治疗方法（如雄激素受体（AR）靶向治疗）的耐药性发展仍然是晚期前列腺癌治疗的主要挑战。迫切需要针对关键耐药驱动因素（如 AR 变体如 AR-V7 和类固醇生成酶，如醛酮还原酶 1C3（AKR1C3））的新治疗策略，以克服耐药性并改善晚期前列腺癌患者的预后。在这里，我们设计、合成和表征了一类针对 AR/AR 变体和 AKR1C3 途径的新型 LX 化合物。分子对接和体外研究表明，LX 化合物结合到 AKR1C3 的活性部位并抑制 AKR1C3 酶活性。LX 化合物还被证明可以降低 AR/AR-V7 的表达并抑制其靶基因信号。LX1 抑制了肿瘤体外酶测定中雄烯二酮转化为睾酮。此外，LX1 抑制了对包括恩扎鲁胺（Enza）、阿比特龙、阿帕鲁胺和达罗鲁胺在内的抗雄激素药物耐药的细胞的生长。当 LX1 与抗雄激素药物和紫杉烷联合使用时，观察到协同作用，表明该联合疗法在治疗耐药性前列腺癌方面具有潜力。LX1 治疗显著降低了肿瘤体积、血清 PSA 水平以及降低了肿瘤内睾酮水平，而不影响小鼠体重。此外，发现 LX1 可克服对 Enza 治疗的耐药性，并且其与 Enza 的联合进一步抑制了 CWR22Rv1 异种移植和 LuCaP35CR 患者来源异种移植模型中的肿瘤生长。总之，LX1 降低 AR 信号和肿瘤内睾酮的双重作用，以及其与耐药模型中标准疗法的协同作用，突显了其作为晚期前列腺癌有价值的治疗选择的潜力。意义：LX1 同时靶向雄激素受体变体和类固醇生成酶 AKR1C3，为克服耐药性提供了一种有前途的方法，并与晚期前列腺癌的标准治疗相结合，增强了治疗效果。
