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Updated: Sep 22, 2025
05:28
A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
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Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability
Moustafa A Shehata1, Julia Contreras2, Ana Martín-Hurtado2
1Kinases, Protein Phosphorylation and Cancer Group, Structural Biology Programme, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain; Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt.
Journal of Advanced Research
|May 20, 2022
Summary
Second-generation RET kinase inhibitors exploit a newly identified post-lysine pocket, enhancing therapeutic strategies for RET-driven cancers by targeting novel druggable vulnerabilities.
Area of Science:
- Biochemistry and structural biology
- Computational drug discovery
- Oncology
Background:
- The structural and dynamic factors governing selective RET kinase inhibition remain poorly understood.
- Targeting the RET active site presents an opportunity for novel cancer therapies.
Purpose of the Study:
- To investigate the druggability landscape of the RET kinase active site.
- To uncover structural and dynamic vulnerabilities for therapeutic exploitation.
Main Methods:
- Integrated structural, computational, and biochemical approaches were employed.
- Molecular dynamics simulations and crystal structure analysis were utilized.
Main Results:
- The RET active site's druggability is dictated by the P-loop and αC helix conformation.
- A novel 'post-lysine pocket' was identified as a druggable vulnerability.
- Second-generation inhibitors (LOXO-292, BLU-667) effectively bind this pocket.
Conclusions:
- The post-lysine pocket represents a significant druggable vulnerability in RET kinase.
- Exploitation of this pocket by advanced inhibitors has implications for drug design.
- This finding supports personalized therapies for RET-driven cancers.
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