Design, synthesis and anticancer evaluation of novel arylhydrazones of active methylene compounds

Area of Science:

• Molecular oncology and drug discovery
• Neuro-oncology and cancer therapeutics

Background:

• Nerve growth factor (NGF) receptor, tropomyosin kinase receptor kinase type A (TrkA), is a key target in Glioblastoma (GBM) due to its role in tumor invasion.
• Current TrkA inhibitors have adverse effects, necessitating novel therapeutic ligands.
• NTRK1 (TrkA) gene expression is elevated in GBM, recurrent GBM, and Oligoastrocytoma, increasing with GBM grade.

Purpose of the Study:

• To identify and characterize novel ligands targeting TrkA for Glioblastoma (GBM) treatment.
• To evaluate the drug-likeness and in vitro efficacy of designed hydrazone derivatives against GBM cells.

Main Methods:

• RNA sequence analysis of 651 brain tumor datasets to assess NTRK1 expression.
• Molecular docking and dynamic simulation studies to investigate the interaction of hydrazone derivatives (R48, R142, R234) with TrkA.
• In vitro cytotoxicity assays using U87 GBM cells and non-cancerous MEF cells, alongside Lipinski's rule of five and oral bioavailability assessment for R48.

Main Results:

• Overexpression of NTRK1 was confirmed in GBM and related brain tumors, correlating with higher tumor grades.
• Hydrazone derivative R48 demonstrated potent binding to TrkA, exhibiting favorable stability, drug-likeness, and oral bioavailability.
• R48 showed significant in vitro cytotoxicity against U87 GBM cells (IC50 = 68.99 μM) with minimal toxicity to non-cancerous cells, though siRNA analysis indicated potential non-specific binding.

Conclusions:

• The hydrazone derivative R48 is a promising lead compound for TrkA-targeted GBM therapy due to its potent in vitro efficacy and favorable pharmacokinetic properties.
• Structural modifications of R48 are warranted to enhance specificity and develop it into a clinically viable TrkA inhibitor for Glioblastoma treatment.