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Updated: May 22, 2026
08:31
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
First-in-class small molecule ROBO2 binders identified through integrated virtual screening and biophysical
Kirti Upmanyu1, Hossam Nada1, Moustafa T Gabr1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY, 10065, USA.
Archives of Biochemistry and Biophysics
|May 20, 2026
Summary
Researchers identified two small molecules that bind to ROBO2, a protein involved in glioblastoma (GBM) progression. This discovery offers a foundation for developing new GBM therapeutics targeting ROBO2 signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Roundabout homolog 2 (ROBO2) is a transmembrane receptor implicated in glioblastoma (GBM) progression.
- Increased ROBO2 expression in GBM promotes tumor cell migration, invasion, and an immunosuppressive microenvironment via Slit2-ROBO2 signaling.
- No small-molecule modulators targeting ROBO2 have been previously reported.
Purpose of the Study:
- To identify and validate small-molecule modulators of ROBO2 for potential glioblastoma therapeutics.
- To establish a screening pipeline for ROBO2-targeted small molecules.
Main Methods:
- Structure-based virtual screening of compounds targeting ROBO2.
- Experimental validation using Dianthus TRIC platform and microscale thermophoresis (MST).
- Molecular docking to analyze binding interactions and identify key residues.
Main Results:
- Two small molecules, Z1334432986 and Z1692774161, demonstrated reproducible concentration-dependent binding to ROBO2.
- Dissociation constants (Kd) were determined to be 41±5 μM and 26±17 μM, respectively.
- Molecular docking revealed a conserved ROBO2 binding pocket and distinct ligand conformations.
Conclusions:
- This study successfully identified novel small molecules that bind to ROBO2.
- The findings lay the groundwork for developing therapeutics to disrupt Slit-ROBO2 signaling in glioblastoma.
- A validated screening pipeline for ROBO2 modulators has been established.
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