Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
Int J Mol Sci. 2020 Nov 5;21(21):8277. doi: 10.3390/ijms21218277.
Resistance to androgen-receptor (AR) directed therapies is, among other factors, associated with Myc transcription factors that are involved in development and progression of many cancers. Overexpression of N-Myc protein in prostate cancer (PCa) leads to its transformation to advanced neuroendocrine prostate cancer (NEPC) that currently has no approved treatments. N-Myc has a short half-life but acts as an NEPC stimulator when it is stabilized by forming a protective complex with Aurora A kinase (AURKA). Therefore, dual-inhibition of N-Myc and AURKA would be an attractive therapeutic avenue for NEPC. Following our computer-aided drug discovery approach, compounds exhibiting potent N-Myc specific inhibition and strong anti-proliferative activity against several N-Myc driven cell lines, were identified. Thereafter, we have developed dual inhibitors of N-Myc and AURKA through structure-based drug design approach by merging our novel N-Myc specific chemical scaffolds with fragments of known AURKA inhibitors. Favorable binding modes of the designed compounds to both N-Myc and AURKA target sites have been predicted by docking. A promising lead compound, 70812, demonstrated low-micromolar potency against both N-Myc and AURKA in vitro assays and effectively suppressed NEPC cell growth.
雄激素受体 (AR) 靶向治疗的耐药性与 Myc 转录因子有关，这些因子参与许多癌症的发生和发展。前列腺癌 (PCa) 中 N- Myc 蛋白的过表达导致其转化为高级神经内分泌前列腺癌 (NEPC)，目前尚无批准的治疗方法。N-Myc 的半衰期很短，但当它与 Aurora A 激酶 (AURKA) 形成保护性复合物时，作为 NEPC 的刺激物发挥作用。因此，双重抑制 N-Myc 和 AURKA 将是 NEPC 的一种有吸引力的治疗途径。在我们的计算机辅助药物发现方法之后，我们已经鉴定出具有很强的 N-Myc 特异性抑制作用和对几种 N-Myc 驱动的细胞系的强增殖活性的化合物。此后，我们通过结构基药物设计方法，通过将我们新颖的 N-Myc 特异性化学支架与已知的 AURKA 抑制剂片段融合，开发了 N-Myc 和 AURKA 的双重抑制剂。通过对接预测了设计化合物与 N-Myc 和 AURKA 靶位的有利结合模式。有希望的先导化合物 70812 对 N-Myc 和 AURKA 的体外测定均表现出低微摩尔效力，并有效抑制了 NEPC 细胞的生长。
