Discovery and prospects of new heterocyclic Isatin-hydrazide derivative with a novel role as estrogen receptor α degrader in breast cancer cells

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.

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.