a Department of Biotechnology, Chemistry and Pharmacy , Università degli Studi di Siena , Siena , Italy.
b Department of Biotechnological and Applied Clinical Sciences , University of L'Aquila , L'Aquila , Italy.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):657-664. doi: 10.1080/14756366.2019.1574779.
14-3-3 are regulatory proteins that through protein-protein interactions (PPI) with numerous binding partners could be involved in several human diseases, including cancer, neurodegenerative disorders, and pathogens infections. Following our research interest in the development of 14-3-3 PPI inhibitors, here we exploited the privileged 4-aminoantipyrine scaffold in the design and synthesis of some derivatives endowed with antiproliferative activity against K-562 cells, and capable of binding to recombinant 14-3-3σ as evidenced by NMR spectroscopy. The binding mode was further explored by molecular modelling, while coupling confocal microscopy with intensitometric analysis showed that compound 1 was able to promote the nuclear translocation of c-Abl at low micromolar concentrations. Overall, 1 is chemically stable compared to parent 14-3-3 PPI inhibitors, and thus emerged as a confirmed hit for further development.
14-3-3 是调节蛋白，通过与众多结合伴侣的蛋白-蛋白相互作用 (PPI)，可能参与多种人类疾病，包括癌症、神经退行性疾病和病原体感染。考虑到我们对 14-3-3 PPI 抑制剂开发的研究兴趣，我们在这里利用了受保护的 4-氨基安替比林支架，设计并合成了一些具有抗增殖活性的衍生物，这些衍生物对 K-562 细胞具有活性，并且能够与重组 14-3-3σ结合，这一点通过 NMR 光谱得到了证明。通过分子建模进一步探索了结合模式，而共聚焦显微镜与强度分析相结合的方法表明，化合物 1 能够在低微摩尔浓度下促进 c-Abl 的核转位。总的来说，与母体 14-3-3 PPI 抑制剂相比，1 具有化学稳定性，因此被确定为进一步开发的有效候选物。
