School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Bioorg Chem. 2024 Oct;151:107665. doi: 10.1016/j.bioorg.2024.107665. Epub 2024 Jul 25.
Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.
与正常细胞相比，肿瘤细胞表现出葡萄糖转运蛋白的上调和糖酵解活性的增加。在之前的研究中，我们通过严格的筛选过程成功鉴定出一种有前途的候选化合物 BH10，它通过靶向葡萄糖代谢显示出抑制癌细胞增殖的强大能力。在本研究中，我们通过生物素化-BH10 的亲和素下拉实验鉴定 Kelch-like ECH-associated protein 1 (Keap1) 为 BH10 的潜在蛋白靶标。随后，我们对一系列 BH10 类似物进行了全面分析，这些类似物的特点是引入了萘并咪唑支架和带有不同末端官能团的三唑环。值得注意的是，化合物 4d 是最有效的候选物，对 HEC1A 癌细胞的抗癌活性更强，IC 为 2.60 μM，在小鼠中的生物半衰期延长，药代动力学特征得到改善（与 BH10 相比）。
