Synthesis and Bioevaluation of 3‑(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities

Glioblastoma is the most common brain tumor, with high
recurrence
and low survival rates. An integrative bioinformatics analysis demonstrated
that anaplastic lymphoma kinase (ALK) is a promising therapeutic target
for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole
derivatives, which were further evaluated for antiproliferative activity
using glioma cell lines. Among them, compound 4a significantly
inhibited the viability of glioblastoma cells. With favorable pharmacokinetic
characteristics and blood–brain barrier permeability, 4a improved the survival rate and inhibited the growth of
orthotopic glioblastoma. The Phospho-Totum system revealed that ALK
was a potential target for the antiglioblastoma activity of 4a. Further experiments indicated that 4a might
be a novel ALK modulator, which interacted with the extracellular
ligand-binding domain of ALK, thus selectively induced ERK-mediated
autophagy and apoptosis. Our findings provide an alternative ALK-based
targeting strategy and a new drug candidate for glioblastoma therapy.