Design, synthesis and biological evaluation of ALK/HDAC dual-targeting agents

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Dual inhibition of ALK and HDACs presents a potential therapeutic strategy for cancer treatment.
• Targeting both ALK and HDACs may overcome resistance mechanisms and improve efficacy.
• Developing novel compounds with dual inhibitory activity is crucial for advancing cancer therapy.

Purpose of the Study:

• To design and synthesize novel dual ALK and HDAC inhibitors.
• To evaluate the inhibitory activity of synthesized compounds against ALK and HDACs.
• To assess the anti-cancer efficacy of the lead compound in neuroblastoma models.

Main Methods:

• Molecular hybridization and pharmacophore merging were employed for inhibitor design.
• Enzymatic assays were conducted to determine IC50 values against ALK and HDACs.
• Cell-based assays using neuroblastoma cell lines (SK-N-BE2) were performed to assess anti-proliferative and apoptotic effects.
• Molecular docking studies were utilized to elucidate the binding interactions.

Main Results:

• Compound 19b demonstrated potent dual inhibitory activity against ALK (IC50 = 8.0 ± 1.2 nM) and HDACs (IC50 = 1.18 ± 0.22 μM).
• 19b showed superior inhibition against the ALK G1202R mutant compared to Staurosporine and Brigatinib.
• In neuroblastoma cells, 19b induced apoptosis and G2/M cell cycle arrest, exhibiting comparable efficacy to existing treatments.

Conclusions:

• Compound 19b is a promising dual ALK/HDAC inhibitor with significant potential for neuroblastoma treatment.
• The dual inhibition mechanism offers a novel therapeutic avenue for ALK-positive cancers.
• Further preclinical development of 19b is warranted for its application in managing neuroblastoma.