Alkheilewi M A, Leach D A, Mohr A, Zwacka R M, Laissue P, Metodiev M, Bevan C L, Van Rensburg M, Pilkington L I, Barker D, Reynisson J, Brooke G N
School of Life Sciences, University of Essex, Colchester, UK.
Department of Surgery and Cancer, Imperial College London, London, UK.
Endocr Oncol. 2025 Jul 8;5(1):e240082. doi: 10.1530/EO-24-0082. eCollection 2025 Jan.
Prostate cancer growth is dependent upon androgens and hence therapies often target this signalling axis. These therapies, for example the antiandrogen enzalutamide, are successful in the majority of men; however, resistance is inevitable and the tumour progresses to the castrate-resistant stage, a disease of unmet clinical need. Consequently, there is a great need for novel therapeutics for castrate-resistant prostate cancer. Thieno[2,3-]pyridine compounds have shown promise as novel anti-cancer molecules, but little is known about their efficacy in prostate cancer. To address this, a panel of thieno[2,3-]pyridine compounds was screened to identify those with cytostatic/cytotoxic activity in prostate cancer.
The effect of the compounds upon prostate cancer proliferation and motility was assessed in a panel of cell lines representing different stages of the disease and non-tumorigenic controls. The effect of the compounds upon cell morphology and cell death was assessed using imaging and flow cytometry, respectively. The efficacy of the lead compound was also assessed in a patient-derived explant model.
The compounds were found to inhibit prostate cancer proliferation and motility, promote G2/M arrest, multinucleation and apoptosis. Importantly, treatment of patient-derived explants with the lead compound DJ160 demonstrated that the molecule inhibits prostate cancer proliferation, even in samples that appear to be resistant to enzalutamide.
Thieno[2,3-]pyridines therefore represent a potential therapy for prostate cancer, even when current therapies have failed.
前列腺癌的生长依赖雄激素，因此治疗通常靶向这一信号轴。这些疗法，例如抗雄激素药物恩杂鲁胺，在大多数男性患者中取得了成功；然而，耐药是不可避免的，肿瘤会进展到去势抵抗阶段，这是一种临床需求未得到满足的疾病。因此，非常需要针对去势抵抗性前列腺癌的新型疗法。噻吩并[2,3 - ]吡啶化合物已显示出作为新型抗癌分子的潜力，但对其在前列腺癌中的疗效了解甚少。为了解决这个问题，对一组噻吩并[2,3 - ]吡啶化合物进行了筛选，以确定那些在前列腺癌中具有细胞生长抑制/细胞毒性活性的化合物。
在一组代表疾病不同阶段的细胞系和非致瘤性对照中评估这些化合物对前列腺癌增殖和运动性的影响。分别使用成像和流式细胞术评估这些化合物对细胞形态和细胞死亡的影响。还在患者来源的外植体模型中评估了先导化合物的疗效。
发现这些化合物可抑制前列腺癌的增殖和运动性，促进G2/M期阻滞、多核化和细胞凋亡。重要的是，用先导化合物DJ160处理患者来源的外植体表明，该分子可抑制前列腺癌的增殖，即使在那些似乎对恩杂鲁胺耐药的样本中也是如此。
因此，即使当前疗法失败，噻吩并[2,3 - ]吡啶也代表了一种治疗前列腺癌的潜在疗法。
Zotero 插件
