Identification, synthesis and evaluation of CSF1R inhibitors using fragment based drug design

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Colony-stimulating factor 1 receptor (CSF1R) is a kinase crucial for macrophage function and is implicated in various cancers.
• Aberrant CSF1R signaling and ligand expression correlate with tumor progression, making CSF1R an attractive therapeutic target.
• CSF1R inhibitors have demonstrated potential in suppressing cancer growth.

Purpose of the Study:

• To identify novel inhibitors of CSF1R using an in silico fragment-based drug discovery (FBDD) approach.
• To screen in-house compound libraries for molecules with affinity to the CSF1R hinge region.
• To synthesize and evaluate potential CSF1R inhibitors derived from identified fragments.

Main Methods:

• In silico screening of approximately 25,000 compounds to identify fragments binding to the CSF1R hinge region.
• Synthesis of 5-nitroindole and 7-azaindole derivatives based on identified fragments.
• In vitro enzyme activity assays to determine CSF1R kinase inhibition.
• Bio- and chemiinformatics analyses for membrane permeability and inhibition properties.
• Molecular docking studies to predict binding interactions within the CSF1R hinge region.

Main Results:

• Six diverse fragments showed affinity for the CSF1R hinge region.
• Synthesized 5-nitroindole derivatives exhibited moderate CSF1R inhibition, while 7-azaindole derivatives showed good inhibition.
• Bio- and chemiinformatics studies indicated superior membrane permeability and enzyme inhibition for 7-azaindole compounds.
• Molecular docking revealed that amino acid residues 664-666 in the CSF1R hinge region are key binding sites for these inhibitors.

Conclusions:

• Fragment-based drug discovery successfully identified 5-nitroindole and 7-azaindole derivatives as promising CSF1R inhibitors.
• 7-Azaindole compounds demonstrate favorable properties for further development as potential anti-cancer therapeutics targeting CSF1R.
• Further optimization and biological evaluation are warranted to develop these fragments into potent CSF1R inhibitors.