PDF(Pubmed)
Abstract：
Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA. Methods: Keeping this in view, we synthesized a series of N\'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds. Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97 µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader.
摘要：
简介:Isatin,杂环支架，是许多抗癌药物的骨架，先前已报道参与多种细胞靶标和机制，包括血管生成,细胞周期,检查点途径和多种激酶。这里,我们报道了一种新型的Isatin衍生物，5i,降解雌激素依赖性乳腺癌细胞中的雌激素受体α（ERα）。Isatin核的这种作用以前没有报道过。他莫昔芬和氟维司群代表雌激素介导的疾病的标准治疗选择，但有其自身的局限性。基于Isatin的三重血管激酶抑制剂BIBF1120（Nintedanib）和多激酶抑制剂Sunitinib（Sutent）已被FDA批准。方法：考虑到这一点，我们合成了一系列N'-（1-苄基-2-氧代-1，2-二氢-3H-吲哚-3-亚基）酰肼衍生物，并在体外评估了它们在MCF-7（ER）细胞系中的抗增殖活性。我们通过Western印迹分析进一步研究了最有效的化合物(5i)对Erα的影响。我们在硅片中使用了药代动力学预测工具，特别是pkCSM工具，以评估化合物的活性概况。结果和讨论:化合物5i在这些细胞中显示出最佳的抗增殖活性(IC50值;9.29±0.97μM)。此外，5i在MCF-7中以剂量依赖性方式下调ERα蛋白水平。通过DataWarrior软件对物理化学性质进行了多方面的分析，揭示了合成化合物的一些突出的药物样特征。对接研究预测了配体(化合物)与靶蛋白(ERα)的结合。最后,分子动力学（MD）模拟表明ERα及其配体5i之间的蛋白质-配体复合物的稳定行为。总的来说,这些结果表明，新的Isatin衍生物5i有望成为新的ERα降解剂。
