前列腺癌仍然是全世界主要的公共卫生负担。 Polo 样激酶 4 (PLK4) 由于其在细胞周期调节和肿瘤进展中的关键作用，已成为前列腺癌有前景的治疗靶点。本研究旨在开发和表征新型姜黄素类似物 NL13，作为前列腺癌的潜在治疗剂和 PLK4 抑制剂。合成了 NL13，并在前列腺癌细胞和小鼠异种移植模型中评估了其效果。激酶组筛选和分子建模确定 PLK4 为主要靶点。通过细胞周期、凋亡、基因和蛋白质分析探索抗增殖和促凋亡机制。与姜黄素相比，NL13 对 PC3（IC50，3.51μM vs. 35.45μM）和 DU145（IC50，2.53μM vs. 29.35μM）表现出更大的效力。 ) 前列腺癌细胞活力和 PLK4 激酶活性（2.32μM 与 246.88μM）。 NL13 通过 CCNB1/CDK1 下调诱导 G2/M 细胞周期停滞，并通过 caspase-9/caspase-3 裂解引发细胞凋亡。这些效应是由 PLK4 抑制介导的，从而导致 AKT 信号通路失活。在小鼠中，NL13 显着抑制肿瘤生长并调节分子标志物，与体外研究结果一致，包括 p-AKT 减少和裂解的 caspase-9/3 增加。NL13 是一种新型 PLK4 靶向姜黄素类似物，通过以下方式发挥有前景的抗癌特性：破坏 PLK4-AKT-CCNB1/CDK1 和细胞凋亡途径。 NL13 代表了一种有前途的前列腺癌治疗新药。© 2024 英国药理学会。

Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer.NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses.Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC50, 3.51 μM vs. 35.45 μM) and DU145 (IC50, 2.53 μM vs. 29.35 μM) prostate cancer cells viability and PLK4 kinase activity (2.32 μM vs. 246.88 μM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3.NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.© 2024 British Pharmacological Society.