Identification of type II and III DDR2 inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Discoidin domain-containing receptors (DDRs) are receptor tyrosine kinases (RTKs) activated by collagen binding.
• DDRs play roles in extracellular signal assimilation and are implicated in breast cancer invasion, migration, and metastasis.
• Targeting DDRs presents a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To develop a fluorescence-based, direct binding assay for detecting type II and III DFG-out binders specific to DDR2.
• To validate the assay's sensitivity and suitability for high-throughput screening (HTS).
• To identify novel high-affinity DDR2 ligands and assess their potential for DDR1 inhibition.

Main Methods:

• Utilized sequence alignments and homology modeling to design a DDR2 construct for fluorescent labeling.
• Developed and validated a direct binding assay for DDR2 DFG-out binders.
• Performed high-throughput screening of a compound library and validated hits using orthogonal activity-based assays.

Main Results:

• Successfully developed a sensitive fluorescence-based assay for DDR2 DFG-out binders.
• Identified high-affinity DDR2 ligands from a compound library.
• A subset of identified compounds demonstrated DDR1 inhibitory activity.

Conclusions:

• The developed assay is effective for detecting DDR2 binders and is amenable to HTS.
• Novel DDR2 ligands were discovered, offering potential for therapeutic intervention in DDR2-related cancers.
• Further investigation into the DDR1 inhibitory effects of identified compounds warrants attention.