Design, Synthesis, Biological Evaluation and Molecular Docking of Novel F-18-Labeled Focal Adhesion Kinase Inhibitors...

Area of Science:

• Medicinal Chemistry
• Oncology
• Radiochemistry

Background:

• Early tumor diagnosis is crucial for effective treatment.
• Focal adhesion kinase (FAK) is frequently overexpressed in various cancers, presenting a viable therapeutic and diagnostic target.

Purpose of the Study:

• To design, synthesize, and evaluate novel FAK inhibitors for potential use as diagnostic radiotracers.
• To assess the in vivo tumor targeting capabilities of F-18 labeled FAK inhibitors.

Main Methods:

• Synthesis of seven novel FAK inhibitors.
• In vitro inhibitory activity assessment (IC50 determination).
• Radiolabeling of lead compounds with Fluorine-18 (F-18).
• In vivo biodistribution studies in S-180 tumor-bearing mice.
• Molecular docking studies to elucidate binding interactions.

Main Results:

• Compounds exhibited potent FAK inhibition, with IC50 values ranging from 1.27 to 1968 nM.
• Compounds 7a and 7c demonstrated nanomolar inhibitory potency (IC50: 5.59 nM and 1.27 nM, respectively).
• [18F]7a and [18F]7c showed significant tumor uptake in mice, with [18F]7c displaying higher accumulation (6.58%ID/g at 30 min).

Conclusions:

• Novel FAK inhibitors with potent activity were successfully developed.
• The F-18 labeled compounds show potential as diagnostic radiotracers for FAK-expressing tumors.
• These findings provide a foundation for developing advanced radiotracers and enzyme inhibitors.