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Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug
Tae Hyun Park1,2, Seung-Hyun Bae1,3, Seoung Min Bong1
1Research Institute, National Cancer Center, Goyang, 10408 Gyeonggi, Korea.
Abstract:
Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers. In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease in phosphorylated MerTK in two lung cancer cell lines. We also determined the crystal structure of the MerTK:AZD7762 complex and revealed the binding mode of AZD7762 to MerTK. Structural information from the MerTK:AZD7762 complex and its comparison with other MerTK:inhibitor structures gave us new insights for optimizing the development of inhibitors targeting MerTK.
Insights
Novel small-molecule inhibitors targeting tyrosine-protein kinase Mer (MerTK) were identified. AZD7762 effectively inhibits MerTK, offering potential for cancer therapy and antiplatelet applications.
Area of Science:
- Oncology
- Pharmacology
- Structural Biology
Background:
- Aberrant tyrosine-protein kinase Mer (MerTK) expression promotes cancer cell survival, invasion, and chemoresistance.
- MerTK is implicated in abnormal platelet aggregation, suggesting its potential as an antiplatelet target.
Purpose of the Study:
- To discover novel small-molecule MerTK inhibitors.
- To validate the efficacy and binding mode of identified inhibitors for therapeutic development.
Main Methods:
- Screening of an in-house chemical library for MerTK inhibitors.
- In vitro homogeneous time-resolved fluorescence (HTRF) assay for inhibition validation.
- Analysis of MerTK phosphorylation in lung cancer cell lines.
- X-ray crystallography to determine the MerTK:AZD7762 complex structure.
Main Results:
- AZD7762, a known checkpoint-kinase (Chk) inhibitor, was identified as a novel MerTK inhibitor.
- AZD7762 demonstrated inhibition of MerTK in vitro and reduced MerTK phosphorylation in lung cancer cells.
- The crystal structure revealed the binding mode of AZD7762 to MerTK, providing structural insights.
Conclusions:
- AZD7762 is a promising MerTK inhibitor with potential dual applications in cancer treatment and antiplatelet therapy.
- Structural insights from the MerTK:AZD7762 complex can guide the optimization of future MerTK inhibitors.
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