School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Bioorg Chem. 2019 Oct;91:103119. doi: 10.1016/j.bioorg.2019.103119. Epub 2019 Jul 15.
The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined.
本研究专注于酰胺连接的喹啉-间苯二酚杂合构建物的设计和合成，作为 HSP90 抑制剂的新型类别。对合成化合物的体外研究导致了化合物 11 的鉴定，该化合物对 HCT116、Hep3B 和 PC-3 细胞系具有有效的细胞生长抑制作用，这是通过 HSP90 抑制实现的。化合物 11 触发 HSP90 客户蛋白的降解，同时伴随 HSP70 的诱导，显示出诱导凋亡的能力，并导致 PC-3 细胞中的 G2M 期细胞周期停滞。分子建模用于将化合物 11 对接入 HSP90 的活性部位，并确定与 HSP90 伴侣蛋白的氨基酸残基的关键相互作用。
